In the aftermath of the bus accident, House struggles with his head injuries and short-term memory loss, and must deal with a concerned Wilson who believes his friend's health may be in danger.

A painter's undiagnosed illness affects his work, and House and his team must look at the man's paintings to determine what's wrong with him.

The team must treat an agoraphobic who refuses to leave his house, and have to work around Cuddy, who is less than thrilled at having hospital equipment relocated. Meanwhile, House is plagued by an itch, and Cameron and Chase have relationship issues.

House and the team take on the case of a woman who collapsed in the middle of a cooking class, and they soon learn she is a highly-renowned cancer researcher who recently gave up her entire career in order to pursue her own personal happiness. Though the team struggles to understand how the woman could give up saving lives for the sake of her own contentment, each grapple with the pursuit of happiness (or lack thereof) in their own lives. As the patient’s condition continues to worsen, so does Thirteen’s as she begins to suffer serious and life-threatening reactions to the experimental Huntington’s Disease clinical trial. Meanwhile, Cuddy attempts to make House’s life miserable for him in retaliation for his part in her own unhappiness.

House and the team are intrigued by Scott, a man whose left brain and right brain operate independently, leaving him with two distinct personalities and no control over some of his actions. As the two sides of Scott’s brain struggle for dominance, his warring personalities make it increasingly difficult for the team to figure out what is causing the unique problem. The team is forced to use some unusual methods to get him to cooperate with their necessary testing. Meanwhile, when House refuses to make an appearance in the clinic, Cuddy takes an unconventional approach to force House to make up the time with a particular patient.

After House’s medical license is reinstated, he reclaims his role as Head of Diagnostics in time to treat Hank Hardwick, an adult film star admitted to Princeton Plainsborough for pulsating eye pain. Meanwhile, Cuddy is reminded that Princeton Plainsborough is not conducive to healthy personal relationships.

On the eve of Thanksgiving, House and the team take on the case of James Sidas, an exceptionally brilliant physicist and author who traded his successful career for a job as a courier. For the ailing patient, intelligence is a miserable burden that has prompted depression and addiction, and this, coupled with a myriad of strange symptoms, nearly stumps the team. Meanwhile the doctors at Princeton Plainsboro wrestle with strained personal relationships.

The team takes on the case of a high school senior who inexplicably blacks out during a class field trip. While in the hospital, the patient repeatedly hallucinates. After exhausting myriad ineffective treatments for her mysterious ailments, House attempts one last controversial approach to diagnosing her: monitoring her cognitive patterns and looking for clues. Meanwhile, Taub airs his dirty laundry at work, and Wilson attempts to furnish his condo.

House and the team take on the case of a woman Julia, who is in an open marriage and becomes ill during a date with her on-the-side boyfriend. As perplexing as the case is, Julia's happy and healthy, yet polygamous relationship is equally baffling to the team. Meanwhile, House tests Wilson's relationship with Sam.

The team takes on the case of an ailing groom-to-be who harbors undisclosed secrets from a previous relationship. As his fiancée tries to get answers to her many questions, a frustrated team winnows down the possibilities. Meanwhile, House spends extra-curricular time with his Princeton Plainsboro colleagues, performing a karaoke rendition of a Gladys Knight & The Pips classic with Foreman and Chase.

Science and faith are called into question when a patient is admitted to the hospital following his reenactment of the Crucifixion. Meanwhile, Taub questions his wife about her relationship with an infidelity support group member, and the team attends a co-worker's wedding.

After saving a stranger who fell onto subway tracks, a man suddenly collapses despite appearing to be unscathed; House tries to avoid a dinner with Cuddy and her opinionated mother.

Cuddy’s mother, Arlene, is admitted to Princeton Plansboro after complaining about unusual symptoms, but stubborn Arlene insists that House be removed from the case, forcing House to come up with non-conventional means to treat his patient.

Thirteen has been in prison for the past year, but the real mystery for House is what she did to get there. At the hospital, the team treats a science teacher suffering from severe respiratory illness. Taub tries to get back into the dating scene, but winds up retreating to his old habits.

The team treats a performance artist (Shohreh Aghdashloo) who deliberately made herself ill with the aim of turning the diagnostics department into her new masterpiece, as House must decide which of her symptoms are real, and which are self-inflicted. As the case progresses, House vows to make changes in his life, but remains rooted in old habits. After the case is over, House finally deals with his anger over the breakup and lashes out by driving through Cuddy's dining room and escaping to a beach.

A teenage boy attempting to follow in his late father’s footsteps as an entertainer is admitted to Princeton Plainsboro with partial paralysis. As the team searches for a bone marrow match, they uncover a disturbing family secret. Meanwhile, House looks for creative ways to remove his ankle monitor so that he can attend a boxing match in Atlantic City, and he treats a patient who is convinced he is suffering from diabetes. Also, Taub faces a tough decision when his ex-wife Rachel tells him that she wants to move across the country with their infant daughter.

Facing a 6-month jail term, and the realization that he won't be there for Wilson at the end, House finds himself examining his entire life while contemplating a dismal future without his best friend.