As the writers'-strike shortened fourth season ended (spectacularly, I might add), House lay in a bed having risked his own life to try to save Amber, Wilson's girlfriend, who had been critically injured in a bus accident after coming to House's drunken aid. Wilson stood at the door of the room House was lying in, having lost his love, and turned and walked away.
When we are re-introduced to the story, Wilson is returning to close up shop, having taken two months of bereavement leave to try to come to terms with Amber's death only to come to the conclusion that he needs to leave.
In addition to Wilson's pending departure, Thirteen's worst fear was confirmed with a positive test for Huntington's in the finale, and she finds herself confronted with the case of a mid-30's career woman whose presence allows for Thirteen to project all of her issues onto the patient.
These two things propel the narrative for the premiere.
Where the episode would at first seem to be fairly typical "House" fare for the first 40 minutes or so, the final segment is outstanding, complete with a sincerely apologetic House assuming blame for Amber's death and repenting to Wilson, who serves as the only affective humanizing force in House's life. The truly great moment of the episode is Wilson's revelation of the true reason he's leaving the hospital--a moment so shocking in it's bluntness that you actually feel sad for the largely unsympathetic House.
The ramifications of the final two minutes of the episode seem like they could pervade House's entire life and dramatically restructure the nature of the show, much like the exodus of House's team at the end of the third season forced the show in a different direction for the fourth season.
I am on edge waiting for the second installment of the fifth season.
At least Tivo means I can rewatch this in the mean time.