House starts the year in prison, serving out a long term for his various misdeeds in Moving On. However, it turns out that he didn't even try to get a lesser sentence and took a one-year term without complaint. He blows a chance for early parole in order to prove a fellow patient's diagnosis. Although he plans to withdraw from the practice of medicine, it appears the real co-dependent relationship is between House and the hospital. With House looking at serving at least another six months, the new Dean of Medicine, Eric Foreman approaches House with an offer to return to work.

House and Cuddy make their relationship public, but despite the fact that they are both happier than they have been for years, they both see problems. House is sure that Cuddy is merely hopped up on the sex and good feelings that are typical early in the relationship and that she will dump him once she realizes what she's gotten herself into. Cuddy is sure that her supervisory role over House is either going to poison their relationship or ruin House's medical skills, and she's uncomfortable with many aspects of House's past, such as the prostitute he's still seeing for non-sexual purposes. House is also not certain he wants to have a role in Rachel Cuddy's life and starts to balk at the responsibility, although towards the end of the season, House and Rachel seem to share a strange bond over a cartoon about pirates.

After finally realizing that his Vicodin habit is distorting his view of reality, House voluntarily enters Mayfield Psychiatric Hospital to detox. However, detoxing turns out to be the easy part - House can't get his medical license back until he's willing to admit his problems run deeper. Although he resists at first, he finally gives in. At the same time, he falls in love, but then finds his paramour has no further interest in him. When he turns to his doctor instead of Vicodin for help, Dr. Nolan realizes he's ready to return to the practice of medicine.