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.
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.
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.
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.
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 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.
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.
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.
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.
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.
