A bus accident leaves House with serious head trauma and partial amnesia. He comes to believe that a patient on the bus had a life-threatening disease and struggles to recall who it was, and what they had.

In the aftermath of personal tragedy, Wilson resigns from the hospital... and from his friendship with House. Meanwhile, Thirteen struggles with her personal medical problems while helping treat an executive assistant with a similar situation to her own.

The team takes on the case of a deaf 14-year-old named Seth who collapsed after he started “hearing” explosions while competing in a wrestling match. When the team tries to test him for seizures, Seth loses vision in one eye, complicating House’s bunk theory of “Exploding Head Syndrome.” As his condition worsens, the team has an ethical disagreement about the patient and his mother’s adamant decision to forego cochlear implants to supplement his hearing. When the prospect of giving Seth the ability to hear for the first time in his life arises, House and the team are faced with a resounding decision. Meanwhile, House’s lack of sleep starts to play tricks on his mind, but he finds his insomnia may be a gift instead of a burden

House returns home to Princeton where he continues to focus on his recovery, but surprises Cuddy with the news that he's making a big change in his life. Meanwhile, the team is unable to diagnose a loud-mouthed video game creator who posts each new symptom on the internet and opts for treatments suggested by the online community rather than by the doctors, and Foreman angles for House's job, but the pressure to solve the case creates tension in his relationship with Thirteen.

A dying patient insists that he has the same disease affecting his heart that killed his father and grandfather at the age of 40. Meanwhile, House discovers that he has a hearing problem while trying to duck student rounds.

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 Valerie, an attractive female executive experiencing random episodes of excruciating pain. House agrees to take the case based on Valerie’s looks, and while treating her, the men on the team are charmed by Valerie’s beauty and personality, with Thirteen looking beyond the superficial to try to discover a link to her illness. Meanwhile, House uncharacteristically attempts to alleviate his conscience by reaching out to a former medical school colleague he wronged.

House and the team take on the case of an avid blogger admitted with sudden bruising and bleeding. From her hospital bed, the patient blogs about her symptoms, doctors and prospective diagnoses to her dedicated band of followers and solicits their advice on a course of treatment. Such openness leads the team to contemplate the value of privacy, especially after House and Wilson uncover secrets from one another 's past. Meanwhile, Chase is coaxed into testing out the dating scene.

House and the team take on the case of Sir William, a "knight" in a closed-off community of men and women living according to the ideals of the High Renaissance. As the team searches the medieval village for environmental factors contributing to Sir William's rapidly deteriorating health, Thirteen and Sir William debate the acts that define honor and loyalty, especially in regard to the "queen" of the community, one of Sir William's most frequent visitors. Meanwhile, Wilson starts over with an ex.

During a session with Dr. Nolan, House recounts the case of a woman who arrives at the Princeton Plainsboro emergency room with an unexplained illness and no recollection of who she is. While trying to solve the mystery of the woman's illness, House must also help her piece together her identity.

A seemingly healthy 14-year-old girl collapses during a skateboarding exhibition; House and Cuddy face the challenge of handling their romantic relationship at work.

When an infant suffers breathing trouble and liver failure, House and the team must look at the medical history of the mother in order to find an answer, and ultimately land on a discovery that forces the mother to jeopardize not only her child's health but her own. Meanwhile Taub and Foreman must find a new female doctor to fill the spot vacated by Thirteen and House and Wilson learn a thing or two about parenting while caring for Cuddy's daughter.

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.

House participates in a school’s Career Day and breaks a few rules by sharing explicit medical stories. Waiting outside the principal’s office, he meets two fifth-grade students who assess House’s relationship woes and try to help him understand how his selfish antics get in the way of showing Cuddy how he really feels.

Tension reaches new heights when Cuddy faces sobering news that propels her to reevaluate her priorities. While House is distracted by his concern for Cuddy’s well-being, the team treats a teenage patient whose worsening symptoms and suspicious body scars indicate more than just physical illness.

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.

After losing a bet with Wilson over a boxing match, House is convinced that his fighter has an underlying medical condition that cost him the fight. While he tries to prove it, he leaves his team alone to help a bomb scientist who suffered a seizure. Meanwhile, House may be experimenting with a new drug to help his leg pain.

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.

House is serving out a lengthy prison sentence for his various misdeeds, including his trip outside the country in an attempt to escape responsibility. Entirely cut off from his old life, House determines his current problems are the result of his inability to deal with people. Feeling he will never be able to practice medicine again, he plans instead to go back to university to earn a doctorate in physics - a field that will all but assure his isolation from other human beings.

A CEO falls mysteriously ill just days before he signs a contract that would relocate his company's entire labor force to China. House attempts to make an underhanded business transaction with his wealthy patient, but when the patient's condition worsens, the team must work around the clock to save his life. Meanwhile, Park prepares for her hearing with the Princeton Plainsboro Disciplinary Committee chaired by Foreman, and Adams' outlook on her patient's business venture reveals her deeper feelings about loyalty.

The team learns that their 14-year-old patient is suffering from more than teen angst when her physical symptoms worsen. Despite Foreman’s firm opposition, House becomes obsessed with solving a peculiar case of a deceased four-year-old patient, which gets him into serious trouble. Meanwhile, Park tries to get Chase to admit the reason behind his recent obsession with grooming.

When a runaway teen requires hospitalization, Adams butts heads with House when she insists they contact Social Services. Meanwhile, Taub has trouble forming a personal connection with his baby daughters and Foreman's relationship with a married woman comes out.

House's green-card wife, Dominika, will return in order to prove to the proper authorities that she and House are actually married. This in turn will lead to a crash course in which both will learn a little something about love and marriage.

House and the team take on the case of a 22-year-old minor league hockey player who collapsed while coughing up blood after a fight on the ice. Meanwhile, House drops a bomb on Wilson, and Chase offers to help Park change her living arrangement.

When House and Wilson disappear off the grid for several days, without explanation, the team is left to deal with a difficult case concerning a 6-year old with numerous problems and complications, including an overbearing mother who also happens to be her physician.

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.