House has recovered from his gunshot wounds and is back at work, taking on two cases simultaneously: Richard (Edward Edwards),^[12] paralyzed after brain cancer surgery eight years ago, who drove himself on his motorized wheelchair headfirst into a swimming pool, and Caren (Clare Kramer),^[13] a young woman paralyzed from the neck down after a yoga session. As House begins to diagnose and treat them, the team notices a distinct change in his attitude toward his patients.

Seven-year-old Clancy (Skyler Gisondo)^[15] is admitted to the hospital with rectal bleeding, claiming alien abduction. The team runs tests, but when they get inconsistent and contradictory results from the same tests, in addition to finding a metal object in his neck, they are forced to give Clancy's testimony a little more credence. Amidst this, Cuddy and Wilson struggle with the fallout from the decision to not to tell House the truth about his last case, thinking he will learn some humility, and Cameron is outraged at their actions when she finds out about the patient. When a frustrated House gives up on the boy, Cuddy is forced to re-think her decision to hold back the truth.

House's new patient is Ezra Powell (Joel Grey), a renowned medical research pioneer who collapses in his lab. House puts Ezra through diagnostic rigors, but the team is unable to come up with a conclusive diagnosis and Ezra's health continues to deteriorate. Ezra ultimately demands the team help him end his life, but each member has divergent opinions on the morality of helping Ezra die, especially since the possibility of a cure is still in question. Meanwhile, Ali (Leighton Meester), the teenage daughter of a clinic patient, has developed a disturbing crush on House.

House takes the case of Adam (Braeden Lemasters),^[18] a 10-year-old severely autistic boy, who screams loudly for no apparent reason. Cuddy makes a minor change to House's office and he refuses to use it until it is returned to its original state; thus, he finds himself wandering the hospital in need of a temporary office. Meanwhile, Ali (Leighton Meester) still has a crush on House and is becoming a nuisance.

House takes the case of a young woman (Jurnee Smollett)^[20] who is rushed to the hospital with problems breathing and severe stomach pain, after she and her husband (Raviv Ullman)^[21] are robbed. But when her husband collapses, the team believes the couple's illnesses are related. Meanwhile, clinic patient Michael Tritter causes problems for House.

A morbidly obese man (Pruitt Taylor Vince)^[23] is found in a coma after a fire accident and is admitted to Princeton-Plainsboro. Upon waking up, he demands to be discharged, refusing to be tested for any disease possibly caused by his weight.

House decides to awaken a patient in a vegetative state (John Larroquette)^[25] so he can question the man regarding the family history of his son (Zeb Newman),^[26] who may have a genetic condition, and the father is the only living relative. Meanwhile, Wilson confronts House about the stolen prescription as Tritter approaches Cameron, Chase, and Foreman in an attempt to divide the team and reveal their loyalties.

House's newest patient is 18-year-old Jack (Patrick Fugit),^[28] brought to the hospital after experiencing a heart attack and massive vomiting. Jack has been the sole parent to his younger brother and sister since their parents died. After a brief review of his file, House thinks he has got the diagnosis, seals it in an envelope and turns the process into a game, challenging Cameron, Foreman and Chase to figure it out on their own. Meanwhile, in an attempt to extract a confession, Tritter makes it impossible for Wilson to practice medicine, driving a wedge between the two friends.

House and the team take on the case of Alice (Alyssa Shafer),^[30] a young girl with pancreatitis. Since her divorced parents cannot agree on how to proceed with her treatment and will not let House bully them into making a decision, House's only option is to take them to court and let a judge rule on the matter. Meanwhile, House's reduced access to Vicodin is beginning to take its toll and he asks Cuddy for more, but instead of writing a prescription, she strictly rations his pills.

It is Christmas at Princeton-Plainsboro and Wilson has a present for House: he and Detective Tritter have struck a deal and House has three days to accept it. Cuddy receives a patient (Kacie Borrowman)^[32] afflicted with dwarfism, who has a variety of symptoms and is recovering from a recently collapsed lung. Cuddy is eventually forced to make a difficult and potentially life-threatening choice between her patient and House's well-being.

House is forced to respond in court to the criminal charges against him regarding illegal possession of narcotics, and the judge sets a date for a preliminary hearing. Cuddy insists that House apologize to Tritter; meanwhile, the most recent case at the hospital is a firefighter (Tory Kittles)^[34] suffering from disorientation and fluctuating body temperatures. Because of misinterpreted information, the firefighter is eventually forced to make a decision to undergo a radical brain treatment which will have a serious effect on his life. His brother (Jason Winston George) takes care of him.

House beats the drug charges and is back at the hospital after a short stint in rehab. Tired of House's disdain for patients, Cuddy turns his clinic duty into a game, with the stakes raised to a level that speaks to House: challenge. When he encounters Eve (Katheryn Winnick),^[36] who is tested positive for an STD and admits she has very recently been raped, she refuses to be treated by anyone but House. Meanwhile, Cameron encounters a homeless man (Geoffrey Lewis) with a critical condition and a very specific request from her.

16-year-old Stevie Lipa (Jake Richardson)^[38] is admitted to Princeton-Plainsboro with a serious respiratory condition and internal bleeding. He is assigned to House, but he is busy fulfilling a dare given to him by Cuddy. When it's revealed that Stevie is Romani and the team encounters troubles with his parents, Foreman is forced to ask Stevie to lie directly to his parents, risking his medical license.

A girl (Mika Boorem) with CIPA, a rare condition in which the sufferer cannot feel pain, gets in a car accident. Once her testing is done, she begins developing high fevers with multiple seizures and is rapidly deteriorating.

A brain-damaged musical savant (Dave Matthews) has seizures despite being on anti-seizure medications. When his team learns that House has entered himself for brain cancer treatment, they attempt to comfort him, but House simply turns them away.

House treats a U.S. Marine (Marc Blucas)^[42] returning from Iraq, who has symptoms consistent with Gulf War Syndrome. However, after House has a dream about the Marine despite having never met him before, the case becomes more complicated, alongside a physical problem that House has to overcome.

Celebrity photographer Emma Sloan (Anne Ramsay),^[44] who is pregnant, is brought to the hospital after suffering a stroke in the middle of a photo shoot. Although Emma's condition initially stabilizes, her health takes a turn for the worse when her kidneys fail. Emma, who had miscarriages in the past and feels this is her last opportunity to have a child, is more concerned about her baby's well-being than her own. Meanwhile, the secret relationship between Cameron and Chase is exposed to Foreman and Cuddy, and House makes extravagant plans to take a much-needed vacation.

House and Cuddy face a widespread outbreak on their plane back from a symposium in Singapore, while Wilson and the rest of the team treat a 58-year old woman (Jenny O'Hara)^[46] with constant seizures who is hiding secrets about her lifestyle.

A six-year-old girl (Bailee Madison)^[48] suffers ailments expected in much older patients. Tensions mount between Chase and Cameron, leading House to intentionally assign them to the same tasks, including investigating the young girl's home, where they find something possibly incriminating on the girl's father. Another clue presents itself in the girl's 8-year-old brother's sexual precocity.

A scam artist (Monique Gabriela Curnen)^[50] loses her ability to make decisions. While House and the team struggle to find the underlying cause, the case becomes personal for Foreman.

A 14-year-old leukemia patient's (Jascha Washington)^[52] only hope of survival is a bone marrow transplant from his younger brother (Dabier),^[53] but when he gets sick, the team must race against time to save both siblings. Meanwhile, Foreman must deal with the consequences of the previous case.

Speculation over Foreman's resignation continues, while a young girl named Addie (Lyndsy Fonseca)^[55] is admitted after bleeding from the mouth during martial arts practice and House and Wilson are secretly concerned about each other.

House meets his match in the form of Nate (Nick Lane),^[57] an obnoxious 16-year-old chess prodigy with intense head pain and behavioral issues, who manages to annoy and offend every member of the team during his course of treatment. Meanwhile, Foreman's frustration with House reaches a new level when he believes House sabotages his job interview with another hospital.

House and the team take on the case of a young woman (Mercedes Renard)^[59] who, along with her husband, is rescued at sea en route from Cuba in a desperate attempt to personally see House and get a diagnosis for her illness. During her stay in the hospital, she develops a new symptom: her heart stops – but she miraculously keeps talking. Foreman prepares for his last day at Princeton-Plainsboro Teaching Hospital.