Although he's lived outside the house from the series's beginning, Francis is a regular character on the show for the first five seasons. His mother, Lois, was in labor with Francis in the middle of her wedding to Hal. Francis was a troublemaker from a young age. He slept around, broke curfew, drank, and smoked. Lois exiled him to a military academy after he was caught in bed with his girlfriend, crashed the neighbor's car (which proceeded to burn up), and got four nose rings. (Lois told him he would go to military academy if he got one nose piercing.) From afar, Francis provides fodder for many subplots. In frequent flashbacks, Francis is shown dating girl of whom his parents did not approve, although he claims to be in love. He has been shown to be obsessive and goes out of his way to show Lois she has no control over him. This enrages his mother immensely, as she believes she should have total control over every facet of her family's lives. He is the most popular amongst his brothers. He himself has stated that he is the brother that the other four like the best.
From the moment he was born, Francis and Lois have been at war with each other. When Francis was 5 years old, Lois was in labor with Malcolm and tried to drive herself to hospital, but Francis believed she was lying and was actually trying to take him to the hospital to give him injections. Francis locked himself in the car singing "Mommy's a liar, Mommy's a liar!", and Lois couldn't get in. As a result, Lois gave birth to Malcolm in her own yard.
During the first two seasons, at the military academy, rebellious Francis finds a formidable adversary in Commandant Edwin Spangler, whose hook-for-a-hand proved a valuable comic device as he sows insurrection in the student ranks. After the second season, at only 17 years old, Francis legally emancipates himself with the help of forged signatures and an unscrupulous Alabama lawyer. He then leaves the academy, accidentally cutting off Spangler's remaining hand in the process, and heads to Alaska to find work as a logger. This incurs Lois' wrath, because she was against Francis leaving school from the start. There, he meets an even bigger foe in Lavernia who runs a tight ship in a logging cabin. He soon finds out that the job isn't as great as Eric said. By the end of Season 3, he leaves him to hitchhike back home as revenge for even suggesting Alaska.
While in Alaska, he marries a local woman, Piama Tananahaakna, after dating her for only a month. Lois reacts hysterically and continues to be somewhat hostile towards her for some time. Piama, like Lois, is hot-tempered and does not shrink when Lois goes after her. By Season 4 Francis and Piama have left Alaska, and Francis finds work as a farmhand at a New Mexico dude ranch owned by a German couple. Here, Francis becomes more of a responsible adult: he even begins to discipline his younger brothers, who always regarded him as a rule-breaking role model. He helps his boss, Otto, deal with the estrangement of his son, Rutger, when he reveals that he was an expert on pointless family conflicts. A little over two years after he begins working at the ranch, however, he is fired because the ATM he used to deposit the ranch's funds was not actually an ATM.
Francis and Piama then lead a life full of different events. Francis becomes an alcoholic and went to AA. Afterwards, he writes a children's book, while Piama gets a job in a snow globe factory. However, Francis can't find a company to publish his book, and Piama finds her job boring and quits. The two of them are once again unemployed.
For the remainder of seasons six and seven, Francis makes only occasional appearances, yet he is still credited in each episode. Later, we find that he has regressed and reverted to his old ways, living in a cheap apartment without getting a job. Here, he briefly takes a job as the agent for his friend's band and attempts to start his own. In Ida Loses a Leg, Lois forces Francis to care for his stubborn, cranky grandmother, Ida, as he's unemployed. Francis and Ida fight like cats and dogs but eventually find common ground in that they both consider Lois a bossy control freak.
In the final episode, Francis and his mother fight over the fact that he remains unemployed. Later, his father discovers that Francis has been working at a large corporation called Amerisys Industries for two months. He explains that he enjoys his job of sitting in a tiny cubicle entering data into computers all day immensely, but he kept the job a secret from his family because he equally enjoys frustrating his mother and doesn't want to give her the satisfaction of knowing he's doing exactly what she would want. Francis' final scene shows him taunting his mother over the phone with his non-existent unemployment by yelling "I'm a FREE SPIRIT!" before he picks up his briefcase, makes plans to come home right after work for dinner with Piama, kisses her, and happily heads to the office.
Even from the earliest age, Francis has been driven by a strong though extremely misguided need for freedom and independence. He is a two-faced rebel. This is basically the driving force of his antics against Lois. With Francis absolutely refusing to allow himself to be controlled by her. According to Hal, Francis' first words were "You shut up!", which was directed at Lois. They even got into a sword fight at the Military School. Lois however is not the only factor, as it is clear Francis greatly hates being controlled ordered in any form.
Francis blames his mother for most of his problems rather than accepting responsibility for them, to the degree that when he is asked to name one thing wrong with his life that he doesn't blame on Lois, he is unable to comprehend the question.
Though Francis and Lois state that they love each other neither of them can truly forgive each other for the misery they've caused each other over the years.
It can be agreed upon that major habit Francis got from Lois and Hal was their tendency to make rash, illogical and out right terribly poor decisions in a quick manner.
Francis can be quite manipulative and despicable. Such as when he purposely made Malcolm and Reese go to war with each other after he purposely only got two wrestling tickets. He then in the end took a girl out instead of either brother.
Despite his recklessness, Francis is sometimes seen as a more thoughtful person, compared to his colleagues. For example, when at the logging camp, he tells Eric that there is more life than just boozing off. He also, at first, refuses to fight Lavernia when she challenges him to duel, after he insults her. Only fighting her when she claims he should crawl back to his mother. Francis also has more violent interaction with Malcolm and Reese, but is very kind to Dewey.
- Hal Wilkerson: Francis and his father have a close relationship. Their relationship is probably Francis's closest relationship of the family. Although Francis was the biggest trouble maker of all the boys, and made it very hard for Hal, Hal does not have a grudge against Francis like Lois does and they do not have a rivalry, like Francis and Lois do. Hal is proud of Francis and appreciates the good qualities he does have. Francis prefers Hal to Lois.
- Lois Wilkerson: Francis and his mother have a rivalry for the whole series and that started before the beginning of the series. Lois has a grudge against Francis for being such a trouble maker as a kid, and Francis resents Lois for not being a good mom to him. Lois does apologize to Francis for not being a good mother to him, but Francis cannot fully forgive her. However, Francis and Lois do care for each other.
- Reese Wilkerson: Francis hates Reese the same way as he does Malcolm. While Malcolm is egotistical, Reese is violent and rowdy. It was stated due to his and Malcolm's bullying of Dewey, Francis often uses violence to get even with the two.
- Malcolm Wilkerson: Francis dislikes Malcolm, due to his big ego, and reveals that he once took Reese and Dewey on a beach trip, and chose not to invite Malcolm. However, he has given Malcolm advice back in Funeral, when he called concerned with their family falling apart. Francis suggested he uses a scapegoat and even mentions that Lois had blamed him for the family's problems.
- Dewey Wilkerson: Dewey is Francis's favorite brother, and he is Dewey's. Due to Dewey being too young, Francis didn't treat him badly, like he did to Reese and Malcolm. Francis's mentoring of Dewey throughout it all is probably one of his few redeeming qualities.
- Piama Wilkerson: Piama is Francis's wife. They met in Alaska when Francis moved there after getting emancipated. Piama is very supportive of Francis though at times they have arguements, as all couples do.
- Eric Hanson: Played by Eric Nenniger, is the friend of Francis who makes his first appearance in the Season 1 finale, Water Park. Eric was the reluctant sidekick to his antics and suffered the consequences during their time in Marlin Academy. When he turns 18, Eric quits school at Marlin and decides to get a job as a logger in Alaska. When Francis legally emancipates himself to join him, he discovers the job isn't great like Eric said because of Lavernia. At the end of Season 3, he and Piama leave Eric to hitchhike back home as revenge for even suggesting Alaska. Eric is never seen again.
- Cadet Finley: Finley is a minor character and friend of Francis during seasons 1 and 2. Finley is reputed to have good grades and was hazed once from a cult group.
- Cadet Drew Drew is a minor character and friend of Francis at Marlin Academy during seasons 1 and 2. Though physically the strongest cadet, Drew is actually emotionally weak.
- Stanley Winn: Stanley is Francis' friend and informal bodyguard during season 1. He has a strong appreciation for the military lifestyle. He is shown doing pull ups whilst having Francis hold on to him to add extra weight. When the majority of the school leaves on an outdoor survival trip, Stanley claims he believes strongly in the trip and threatens to break Francis' clavicles if he does not attend. Later when cadets are showing off their survival skills based on how little equipment they are bringing, Stanley enters the room completely naked except for camouflage paint over his entire body and a knife fastened to his back.
- Richie: Richie is Francis' best friend before military school, and Francis often visits him on his trips back home during the first two seasons. He is a vagabond and delinquent who was eventually shipped off to military school with Francis. Richie was Reese's boss in a fast-food restaurant called "Circus Burger", where he stole hundreds of dollars from the cash register. He framed him for the theft until Malcolm and Barton, a classmate of his(whom Richie kept mistakenly referring to him as Dewey due to their similar age) proves his innocence. It is never explained why Richie disappears or why Francis never sees him again after the third season. He once gave Francis an injury by clipping his nasty toenails and hitting Francis in the eye with it. He is last mentioned in the season 6 episode "Stilts" by Francis, claiming he tried to dry off Reese in the oven after he had taken several different pills at once. He had two other friends named Circus and Justin. Richie is mentioned in the episode Stilts, where Reese is on drugs, and phones Francis to help him with his addiction. Francis says "You're on drugs !? Haven't you learned anything from my friends? Remember when Richie was babysitting you and he put you in the oven and cooked you?"
- Donnie: Donnie is a friend of Francis whom taken over the house with his gang of drug addicts in the hopes of turning it into a crystal meth lab. It was revealed that he has no control over Donnie and it ended up being Dewey to solve the problem by secretly calling Donnie's mother and the others. Donnie was displeased to see his mother in front of him, giving her a piece of his mind. He hasn't been seen since then.
- Artie Artie is a chubby, uneducated, color blind and dyslexic employee at the Alaskan lodge. Artie often hung around with his co-workers Pete, Francis and Eric. It is implied that Artie may have absorbed his twin in the womb, as he mentions that he had a boil removed, but it turned out to be the vestiges of his unborn twin. While he seems to fit in and get along with them, Eric states in "Jury Duty" that Artie is the "camp outcast". It is unknown what happened to him after the lodge was shut down.
- Pete: Pete is an elderly employee at the Alaskan lodge. He usually hung around with his co-workers Artie, Francis and Eric. Pete seems to be possibly insane, or at the very least senile, as he often says bizarre, outlandish things (such as hinting he's spent a night in a caribou's stomach or believing bears can fly and lay eggs). Because of this, he is often looked upon as an "old coot". According to Eric in "Jury Duty", Pete has a family, but they apparently abandoned him and changed their names so Pete could not track them down. When the lodge is shut down, Pete wearily says that he'll probably have to move back in with his parents.
- Otto Mannkusser: Otto is the cheery and friendly boss of Francis who owns the Grotto Ranch during seasons 4 and 5. He tries to protect his boss from being taken advantage of from his other co-workers due to his gullible nature. Otto is married to Gretchen and has an estranged son named Rutger, whom Francis helps to reconcile with using the aid of a sock puppet (Schlupi). Otto is very gullible, once even buying 200 dollars worth of sunscreen for cows, even though cows do not need sunscreen. However after working at the Grotto ranch for a little over two years, Otto fires Francis when the ATM that he was depositing his funds into was not really an ATM. Otto's actor, Kenneth Mars, died aged 75 on the 12th of February 2011. You can read his online obituary here
- Circus: Thinks Francis is 'the man'.
- Gretchen: Second boss to Francis at the ranch and wife to Otto. Francis and Gretchen seldom interact without Otto's presence.
- Lois: Francis and his mother, Lois have an ongoing feud, having yelled and screamed at each other for as long as time can tell. Although this is kind of true about all of the Wilkerson brothers, Francis has to be the one with the most passion in his hatred with her. He has argued with her the most, and has intentionally gone out of his way, to rebel against her, with the only reason being to spite her. Francis' main conflict with Lois is that she doesn't let him be a "free spirit" and controls him around all the time. His main goal in his rivalry with her is to disobey her commands and live his life the way he wants to. Lois had big plans for Francis' future and he enjoys tormenting her by rebelling against her wishes
- Commandant Spangler: Commandant Spangler is the strict, hard-nose disciplinarian at Marlin Academy. He often buts heads with Francis because of his insurrection and rebellious nature. However, Francis doesn't prove to have much anger or hatred being held toward Spangler. In fact, he hates Lois for sending him to Marlin Academy more than he hates Spangler, himself. This allows Francis to be a bit more happy and care-free when being mean to Spangler, because he can have a little fun, breaking the rules and completely driving Spangler insane. Francis eventually left Marlin Academy, but when he did, Spangler missed him deeply because he was the only cadet who actually learned something from him. In the episode Dewey's Dog, a recently fired Spangler hunted down Francis and Eric and eventually found them at the log cabin and begged for him to come back. However, Francis manages to find Spangler a job at a local retirement home which allows him free reign to bully the elderly.
- Lavernia: Lavernia was the malevolent and heartless boss of Francis for the majority of Season 3. She ruled over him and Eric with an iron fist. Francis very quickly grew to hate Lavernia and had a lot more anger for her than he did for Spangler. After Francis married Piama, she wanted to stand up to Lavernia for abusing her husband. Piama secretly stole Lavernia's pet parakeet and held it for ransom, ordering her to treat him better or else. When Francis found out, he thought that Piama was taking it too far with that scheme and attempted to return the parakeet to Lavernia, but it froze to death along the way, incurring her wrath. After this, Lavernia fired everyone at the logger cabin and shut it down, ending her interactions with Francis forever.
- Ida: Francis' hatred for Ida is almost as strong as his hatred for Lois and Ida returns the favor. Francis has been forced to live with and care for Ida a few times in the series, such as Christmas and Ida Loses a Leg and he hates taking care of her, just as much as she hates being taken care of him. Francis thinks Ida's a disgusting, racist, old bag and he can't wait for her to finally die. He even tried to kill her in the episode Graduation. However, by sharing such similar feelings with Francis, she also shares the same hatred for Lois with him, giving them some common ground to agree upon.
Francis' first known job was working as a cadet in a military school in Alabama called Marlin Academy. Francis hated every second of working there, and what he hated the most was his superior. An army general named Commandant Spangler. But, Francis had to work there because he was a crazed delinquent who had no sense of morals and his parents had no choice but to send him there. He worked here for the first two seasons, until the episode Houseboat, where he got himself emancipated from his family so that he could legally leave the academy and live a life of his own.
In the episode Charity, which is a few episodes later, Francis moved to Alaska, where he started working in a kitchen for an equally terrible boss named Lavernia. He hated her just as much as he did his old boss. However, he was able to be a bit more dominant against her in episodes such as Health Scare, as Lavernia was not as strong and powerful as Commandant Spangler was, so he was a tiny bit happier with his new job. This is also where he met his wife, Piama as seen in the episode Hal's Birthday. In the season 4 opener, Monkey, Francis finally gets enough money to quit his job as a worker at the restaurant and moves back to New Mexico with Piama.
In the episode Zoo Francis and Piama start working at a Cattle Ranch in New Mexico, which is owned by a German couple named Otto and Gretchen Mannkusser. Unlike his previous two bosses, Otto and Gretchen are extremely nice and easy going with him and they treat him with the upmost of respect. However, the two of them are a bit too nice to their other employees, as they give the other employees excessive amounts of vacation days. Francis is the only one there who doesn't intentionally take advantage of Otto's niceness, but being as reckless and destructive as he is, he needed Otto's niceness to keep that job. Francis' niceness to Otto was also sort of a bad thing on his behalf, because he was left to do all the work, that the other employees woudn't do.
In the episode Hal's Christmas Gift, after two and a half years of working at The Grotto, Francis is finally fired when he loses all of the company's money, by getting rid of all of it in what he thought was an ATM (what it really was is never specified). After this, he and Piama are both out of a job and had to live in a crummy old aprtment room.
Although he mainly spent his life being unemployed at this point, he has gotten technical "jobs" which only last for one episode. In one episode, Francis briefly gets a self-promoted job as an agent for his friend's band, but is never seen or mentioned having that job again, with the reason for him losing it, going unknown. In the episode Ida Loses a Leg, Lois gives Francis the quote on quote "job" of being a caretaker for Ida because of the fact that he was the only unemployed member of the family, but he quits that job too at some unseen and unmentioned point.
In the episode Graduation, Francis was revealed to have finally gotten an amazing job at AmeriSys Industries. Francis wanted to keep this a secret from Lois because he didn't want to give her the satisfaction of letting her know that he got a job. Instead, he wanted to spite her with the "fact" that he was never going to become employed because as he mentioned, he's a "free spirit". Hal is the only one in the family who knew about this. After this, Francis pretty much spent the rest of his days making tons of money off of his great job and occasionally pretending that he was still an unemployed old bum in front of his angry, disapproving mother, Lois.
- Lois went into labor with Francis in the middle of their wedding, but Lois pushed herself not to give birth to him until they were legally married, in order to keep him from being born out of wedlock, as seen in the episode Flashback.
- He is the only worker at the Cattle Ranch who is actually American.
- In Season 4's If Boys Were Girls, Masterson is the only actor who portrayed his female counterpart, Frances. In it, she was supposed to go to college, but like her male counterpart, she rebelled against Lois' wishes by dropping out of college and marrying a trailer park man (possibly a male counterpart to Piama). Frances and her sisters all gang up on her by taking out their frustration on their mother. Also like her male counterpart, Frances blames Lois for all her marital problems just because she can't take responsibility for them herself.
- Actor Aaron Paul auditioned for the role of Francis, but did not get the part. Ironically, Aaron Paul would later get a starring role (along with Malcolm in the Middle actor Bryan Cranston) in the AMC Drama Breaking Bad.
- Francis's picture is the first face to be shown on Malcolm in the Middle, if Reese's left nostril doesn't count.