When doctors are unable to diagnose why a severely autistic boy screams loudly for no apparent reason, House takes the case. As the boy's condition worsens, it becomes obvious that House relates to the boy because he has no social niceties.

On House and Cuddy's flight from Singapore a passenger gets ill and Cuddy suspects an epidemic. At the hospital, Wilson leads the team as they deal with a middle-aged woman suffering from seizures.

House finds that some of his own fellowship students will do whatever it takes, when they deal with a woman who believes she can talk to the dead.

House copes with a patient whose symptoms conceal a greater problem, but spends much of his time dodging Cuddy's orders to give performance reviews, and fighting with Amber over who gets to spend more time with Wilson.

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.

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

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 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.

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 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.

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.

Over the years, during the course of performing autopsies at Princeton-Plainsboro, Dr. Peter Treiber has often identified mistakes made by physicians that caused the patient's death. These observations have left him questioning the skills of nearly all the doctors on staff... all, that is, except House. When he falls ill, he demands that only House make medical decisions concerning his care. Unfortunately, House and Wilson have taken off on an impromptu road trip without telling anyone, leaving the team to fend alone and lie to their patient to make him believe that House is the guy calling all the shots.