When a newborn disappears from the nursery, Princeton Plainsboro goes on lockdown, preventing anyone from entering, leaving or moving within the hospital. While House and his team members are trapped in various parts of the building, new insights about the team’s personal histories, relationships and regrets surface.
House and the team rush to treat an ailing college football star in time for the patient to compete in NFL tryouts. But when the patient experiences an onslaught of varied and unusual symptoms, the team has trouble reaching a consensus on how to effectively treat him in time. Meanwhile, Foreman’s brother Marcus makes a surprise visit to the hospital.
During a day in the life of Princeton Plainsboro's Dean of Medicine, Dr. Lisa Cuddy, the inner workings of the hospital are seen through her eyes. This day proves to be especially trying as Cuddy wrestles with myriad hospital issues and staff disputes that test her perseverance and skills as an administrator, all while juggling issues in her personal life.
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.
When drug dealer Mickey mysteriously collapses while negotiating a sale, his partner-in-crime, Eddie, accompanies him to Princeton Plainsboro for treatment. But with a major deal pending, Mickey is not forthcoming with the necessary personal information the team needs to treat him. As Mickey's condition worsens, the team resorts to old-fashioned detective work to solve the case. Meanwhile, House and Wilson compete for the affection of a new neighbor, and Chase, Thirteen and Taub attempt to play a practical joke on Foreman.
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.
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.
When an old friend and former patient of Wilson’s exhibits paralysis in his right arm, Wilson puts himself on the case. House wagers Wilson that the patient’s symptoms are attributed to new cancer cells. Wilson accepts even though he is reluctant to believe the cancer has returned. With the help of the team, Wilson works to diagnose the patient more optimistic results, but when things take a turn for the worse, Wilson must address his inability to separate patient from friend. Meanwhile, Cuddy seeks advice in her search for real estate.
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.
After a wild night out, a teenage girl is brought to Princeton Plainsborough with severely swollen appendages. The team must work to diagnose the young girl, who is less than honest about what happened the night she fell ill. As her condition worsens, she becomes unable to distinguish fact from fiction. Meanwhile, Cuddy, Wilson and House spend a weekend away from the hospital to attend a medical conference, but things don’t go as planned when House’s private investigator, Lucas returns.