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.

House and Cuddy are exploring the ramifications of those feelings and attempting to make a real relationship work. Meanwhile, due to a colleague's illness, Princeton Plainsboro is left without a neurosurgeon on site, threatening the hospital's accreditation as a Level 1 Trauma Center. As the team attempts treatment to get their sick colleague back to work, they discover there is more to the illness than they originally suspected and turn to House for direction. Instead, House remains elusive, leaving the team on its own.