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.

House and the team take on the case of a woman Julia, who is in an open marriage and becomes ill during a date with her on-the-side boyfriend. As perplexing as the case is, Julia's happy and healthy, yet polygamous relationship is equally baffling to the team. Meanwhile, House tests Wilson's relationship with Sam.

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.

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 children's novelist tries to kill herself, but is thwarted when she has a seizure. House, a fan of the books, puts her on psych hold but has to deal with a patient that is eager to die rather than be cured. Meanwhile, House worries that he'll lose Cuddy because they have nothing in common.

After a 200-year-old medicine jar found on an off-shore shipwreck shatters in a teenage girl's palm, she is admitted to Princeton Plainsboro for symptoms closely linked to smallpox.

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.