Two months have passed since Amber Volakis's shocking death. Unable to cope, Wilson resigns from the hospital, while Cuddy desperately tries to get him and House to repair their shattered friendship. Meanwhile, Thirteen struggles with her own diagnosis of Huntington's and helps to treat an executive assistant (Christine Woods) with a similar personality to her own.

An organ donor's organs are responsible for the deaths of several patients, and the team works against the clock to save the last two recipients. Meanwhile, House hires private detective Lucas (Michael Weston) to spy on Wilson, as well as his team, during the differentials.

A painter's (Breckin Meyer) undiagnosed illness begins to affect his work, but he is unable to see his art is suddenly grotesque. He is brought to Princeton-Plainsboro Hospital, though he claims that he is getting better. House grows suspicious when he learns that the painter was fearful of a test involving the injection of a dye. It is later revealed that he is on three separate drug trials, which he was hiding from his girlfriend. Meanwhile, House continues to use Lucas to obtain information about his team and to learn more about Cuddy's personal life.

Final diagnosis: Food Bolus Bezoar complicated by massive experimental pharmaceutical drug intake

House is coerced into going to his father's funeral despite his protests. His team takes on the case of a young woman (Samantha Quan) who collapsed while in China searching for her birth parents. House works with the team via cell phone, while Wilson drives him—reluctantly—to the funeral. House's phone is taken by a cop mid-diagnosis and the team must decipher House's last statement. Meanwhile, the story of how House and Wilson met for the first time is revealed.

Thirteen takes a woman (Angela Gots) with whom she had a one-night stand to Princeton-Plainsboro after the woman has a seizure in Thirteen's apartment. House and the team take on her case, House using it as an opportunity to explore Thirteen's personal life. Thirteen ends up finding out the patient only slept with her to get to House, who had been rejecting the woman as a patient for many years. Meanwhile, Lucas continues on Wilson's trail.

The team take on the case of a middle-aged man (Salvator Xuereb) who has been experiencing recurring blackouts, time lapses and sleepwalking. They soon find out that the man's 12-year-old daughter (Joanna Koulis) has also been experiencing sleepwalking spells. The man's condition deteriorates and his daughter also begins to experience more symptoms. Meanwhile, House finds out Cuddy is going to adopt a baby that is due in two weeks. However, the birth mother (Vanessa Zima) has a strange rash on her arm, so Cuddy takes on her case as both a doctor and a potential mother.

An agoraphobic man (Todd Louiso) falls ill and refuses to leave his home to be treated at the hospital. Therefore, House and the team go to his home to figure out what might be wrong. Cameron takes charge of the case as she had treated the patient in the past and she and the team figure out ways to treat him at his home. However, the patient's condition worsens and it becomes difficult to treat him at his home. House and the team plan to get the man into the hospital for surgery without causing any problems. Meanwhile, Cameron and Chase attempt to work through issues in their relationship, and House deals with an annoying itch he cannot seem to scratch, with Wilson making his own analogies about the problem.

The team takes on the case of a 16-year-old factory manager (Emily Rios) who collapsed when her lungs suddenly filled with fluid while at work. The teenager informs House and team that she has been an emancipated minor ever since her parents died. Meanwhile, Foreman asks for House's permission to work on a clinical trial and House rejects his proposal. In an effort to prove himself capable of working without House's supervision, Foreman takes on his own pediatric case. But when the unexplained illness brings the child (Kyle Red Silverstein) to the brink of death, Foreman is left questioning his ability to work free from House's custody.

A man (Željko Ivanek) takes over Cuddy's office and holds House, Thirteen, and several patients hostage, demanding a diagnosis. To make sure that the doctors are not going to sedate him, he forces Thirteen to act as a guinea pig for his treatments. House has to find a way to end the standoff before Thirteen becomes seriously ill, and before SWAT start their assault.

A fitness guru (Samantha Shelton) known for her "natural" lifestyle collapses while shooting an infomercial. Meanwhile, Thirteen participates in a clinical drug trial for Huntington's disease led by Foreman; Kutner operates an online medical-advice clinic under House's name; and Cuddy moves into House's office while hers is being repaired, much to House's dismay.

A troubled teen (B. K. Cannon) collapses during her high-school Christmas program; Foreman and Thirteen learn more about each other as they work together on the Huntington's disease drug trial; House gives and receives holiday gifts, leading to team speculation; and Cuddy receives a gift as well.

At Cameron's urging, the team takes the case of a suicidal man (Martin Henderson) who suffers from excruciating chronic pain—pain that mirrors House's. Meanwhile, Cuddy discovers that caring for her new foster baby leaves her little time to run the hospital; and Foreman and Thirteen continue to explore their complicated relationship as they work together on their Huntington's disease drug trial.

Cuddy decides to spend more time at home to take care of her new foster baby and gives Cameron the responsibility of overseeing House. The team treats a special education teacher (Erika Flores) whose seemingly inherent goodness is actually a pathology. Foreman must make a potentially dangerous decision about Thirteen's participation in his drug trial.

House and the team take on the case of a woman (Judith Scott) who collapsed in the middle of a cooking class. When they learn that the patient gave up her career as a highly renowned cancer researcher in order to pursue her own personal happiness, the members of the team question their own happiness (or lack thereof). Meanwhile, Thirteen begins to suffer serious and life-threatening reactions to her experimental Huntington's disease clinical drug trial, and Cuddy retaliates against House and gives him a taste of his own medicine.

When a priest (Jimmi Simpson) who runs a homeless shelter sees a bleeding Jesus hovering at his doorstep, he is admitted to the ER. House takes on the case as a distraction for the team while he confronts Foreman and Thirteen about their relationship. The team soon learns the priest had been involved in a molestation scandal that caused him to lose his faith. However, just as they are about to dismiss his case, the patient's condition takes a drastic turn for the worse, and House grapples with his past and his own personal beliefs.

The team encounters a teenage boy (Dominic Scott Kay) who collapsed from severe pelvic pain after playing basketball. The boy was born with a condition called genetic mosaicism (46, XX/XY), or both male and female DNA, and the boy's parents inform House and the team that the boy is unaware of his condition. They chose a gender for him when he was born and raised him accordingly. However, when his condition worsens and his life is threatened, the parents wonder whether they made the right decision. Meanwhile, Cuddy and Wilson suspect something is wrong with House when he starts acting way too nice.

House and the team take on the case of Nick Greenwald (Jay Karnes), a book editor who loses his inhibitions and starts insulting co-workers at a dinner party one night before falling ill. The team realizes Nick has frontal lobe disinhibition, which has caused him to lose his filter and vocalize all of his innermost thoughts, resulting in extremely insulting outbursts. As Nick's free speech leads to some amusing and insightful comments regarding the team, he must deal with the consequences of being unable to lie to his wife and everyone else important in his life. Meanwhile, House suspects Wilson and Taub are keeping something from him when he catches them both in a lie.

Nursing-home worker Morgan (Judy Greer) fakes illness to get House's attention after the home's pet cat, Debbie, sleeps next to her. It seems that Debbie only pays a visit to people if they are about to die and does so with alarming accuracy. While House dismisses Morgan as a nut job, he is intrigued by her theory on the kiss-of-death cat, and sets out to disprove it. When Morgan falls seriously ill, he and the team are forced to get to the bottom of both mysteries. Meanwhile, Taub struggles with his finances and reconnects with an old high school friend at the clinic whose business successes present Taub with an entrepreneurial opportunity he had not previously considered.

House is injured in a motorcycle accident in New York and finds himself in bed next to a patient (Mos Def) suffering from complete paralysis from a bicycling accident. As House transfers the patient to Princeton to determine what's wrong with him, Wilson tries to find out why House was in New York in the first place.

An older woman, Charlotte (Colleen Camp), who has been taking care of her husband Eddie (Meat Loaf) for the last six months, is rushed to Princeton-Plainsboro for treatment after collapsing at Eddie's deathbed from respiratory failure. The case is further complicated as Eddie's condition improves while Charlotte's deteriorates. Meanwhile, the team tries to deal with their grief over Kutner's sudden suicide.

Staff at Princeton-Plainsboro, particularly House and the team, try to deal with Kutner's recent suicide while Cameron presents House with the case of an environmentalist (Tim Rock) who collapsed in the middle of a protest. Meanwhile, Cameron cancels a trip that Chase had planned for them and spends the next few days avoiding him for a surprising reason.

A deaf 14-year-old boy, Seth (Ryan Lane), collapses in the middle of a wrestling match after "hearing" explosions. House suffers from lack of sleep, which causes him to hallucinate that Amber is with him, helping him to solve the case. House also plans Chase's bachelor party — much to the dismay of Cameron — with the help of Amber. But House soon realizes that Amber is dangerous, and that she is not helpful to the case when Cuddy calls him to let him know that his diagnosis was wrong. The team goes to the hospital after the bachelor party ends suddenly to figure out what is wrong with their patient — after they sober up.

House and the team are given the challenging case of a ballerina (Jamie Tisdale) whose lungs collapse during a rehearsal. After first facing the prospect of never dancing again, the ballerina's future seems even more grim when the treatment causes her skin to fall off. House must solve this daunting puzzle while going to desperate measures to cure his hallucination; he continues to suffer from a severe lack of sleep and is still haunted by Amber. While enlisting Wilson's help to diagnose himself, he is willing to do the unthinkable to make his visions stop.

House and the team are intrigued by Scott (Ashton Holmes), a man who has undergone a corpus callosotomy procedure to treat epilepsy. Due to this, both sides of his brain are at war for dominance over the body resulting in him having Alien Hand Syndrome where he can't control his left arm. At the same time Cuddy and House try to deal with their relationship after spending the night at his apartment. The next day, House tells Wilson that he has stopped taking drugs and had sex with Cuddy, to which Wilson responds "Wow". But he also tells him that Cuddy may be repressing her feelings for him, and is trying to avoid him. Finally House realizes that his night with Cuddy and her helping him to stop his addiction to Vicodin was all an elaborate hallucination. With his hallucinations spiraling out of control, House is forced to go into a mental health facility after becoming unable to tell fantasy from reality.^[29][30]