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.

House and the team take on the case of a ballerina whose lungs collapse in the middle of a performance. When the treatment causes her skin to fall off, the dancer faces not only the prospect of never dancing again but also of dying an agonizing death. The team must use their imaginations to carefully choreograph ways to test and treat her delicate body without killing her. Meanwhile, House continues to suffer from what he thinks is insomnia, and he is willing to go to desperate measures to cure it.

A man awakens in New York after a bicycle accident unable to move or communicate in any way. House, himself injured in a motorcycle mishap, occupies the hospital bed next to Lee and quickly annoys the doctors treating them both by insisting that Lee has “locked-in” syndrome.

Charlotte, an older woman who has spent the last six months taking care of her dying husband Eddie, is rushed to Princeton Plainsboro after collapsing from respiratory failure. The couple becomes a double mystery for the team when Eddie begins to improve as Charlotte’s condition worsens. The previously unthinkable becomes real when it seems that Charlotte will die before Eddie, and the team will be forced to make a difficult decision.

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

While en route to his father's funeral, House must help the team with a differential diagnosis on a young Chinese girl who has collapsed under mysterious circumstances.

A gun-wielding man from the waiting room at the Princeton-Plainsboro clinic takes House, Thirteen and several patients from the waiting room hostage in Cuddy's office. The man claims to be sick with a long undiagnosed illness and demands medical attention from the best doctor in the hospital, threatening to kill any hostages necessary along the way.

House and the team take on the case of Nick, a book editor who loses his inhibitions. The team realizes Nick has frontal lobe disinhibition, which causes him to speak his mind having no control over what he says and making him just like House. Meanwhile, House suspects Wilson and Taub are keeping something from him.

An ailing man suffers from blackouts and sleepwalks, leading the team to wonder if his sleepwalking is a symptom, or how the man is becoming exposed to something else. When the man's daughter grows ill as well, the team must provide a diagnosis before both die. Meanwhile, Cuddy adopts a newborn but when the birth mother displays a rash, she has to make a decision between putting the mother or daughter at risk.

A patient with both male and female DNA has the team stumped. Meanwhile, House starts acting nicely, raising Cuddy's and Wilson's suspicions that something is terribly wrong.

Thirteen brings her one-night stand to the hospital after the woman has a seizure. However, the woman admits she slept with Thirteen just so she could get to House and have him diagnose her condition. Meanwhile, House continues to pay Lucas to spy on Wilson.

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.

When a priest 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 belief

House and his team deal with a bullied girl who collapses during her school's Christmas program. Meanwhile, Foreman and Thirteen grow closer during the Huntington's disease drug trials, House gives a patient a gift, the staff wonder who gave House a special gift, and Cuddy gets an unexpected gift.

Cameron postpones her vacation with Chase in order to ask House to accept the case of an environmental radical who collapsed at a protest with unexplainable symptoms. Although suspicious of her motives, House agrees. Since she pushed him to take the case so emphatically, House forces Cameron to take the lead and run many of the tests on the patient. Meanwhile, House is unsure of Wilson’s new healthy diet.

The team deals with an organ donor whose organs prove fatal, and the two surviving patients. Meanwhile, House hires a private detective to spy on Wilson, but hears a few things about himself that he'd rather not.

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.

The team takes on the case of a fitness guru on an all-natural diet who collapsed while filming a video. Meanwhile, Foreman conducts Huntington's Disease drug trials and Thirteen signs on as a subject, Cuddy is forced to move into House's office, and Kutner uses House's name to run an online medical-advice website.

Morgan works in a nursing home with a pet cat who only sleeps next to people if they are about to die - and does so with alarmingly accuracy. When it seems the cat has predicted her own death, Morgan, convinced she is about to die, fakes a seizure in order to get to House to have him diagnose her before it’s too late.

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.

While Foreman takes on a pediatric case on his own, the rest of the team deals with a 16-year-old factory manager and emancipated minor who collapses at work. When Foreman's patient takes a turn for the worse, he's forced to question whether he can deal with the situation on his own, or if he needs House's help.

House and the team try to diagnose a man living with severe, chronic pain; Thirteen and Foreman explore their complicated relationship; Cuddy discovers that caring for her baby leaves her with little time to run the hospital.

Cuddy decides to spend more time at home to take care of her newly adopted baby and passes some of her day-to-day responsibilities off to Cameron, including supervising House. Cameron is forced to play House’s games and becomes involved in a power struggle as he and the team take on the case of a Special Education teacher who collapsed after spitting up blood in the middle of class. As House tests Cameron’s tolerance for his extreme measures, the patient continues to fall ill and House insists the teacher’s seemingly inherent goodness is actually a pathology.

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.