After a fatal car accident, a man, a woman and their son are patients in the Seattle Grace hospital. The injuries of the mother reveal a family secret. Another patient has swallowed something strange, but refuses to reveal what. On the personnel level, Meredith and Cristina try to get along with the ending of their relationships. While Meredith tries to avoid Shepherd, Cristina and Burke are involved in the same medical cases. George feels uncomfortable still working with Olivia, who wants him to forgive her. Derek also reveals why he left New York.
Meredith's mother is admitted to the hospital, revealing that the once great surgeon now has Alzheimer's disease. Menwhile, Christina faints during operation and needs immediate care. She loses her baby due to complications and becomes a patient. Burke finally finds out about her pregnancy when it's too late. Mrs Grey gives hell to George because she thinks he is her husband, but George copes with it.
A storm rages in Seattle. Izzie is very disappointed by her date with Alex, and Meredith is upset with Derek. They both complain to George, which drives him crazy. At the hospital, Cristina has a patient that uses porn as a pain killer and Meredith takes care of an Asian girl who needs to see a Shaman before surgery. There is a power shortage and George and Alex are stuck in an elevator with a critical patient. They need to perform heart surgery, but Alex is too freaked out and so George does it.
A train wreck brings multiple casualties to Seattle Grace, leaving Meredith hanging for her answer. Meanwhile, Alex finds working without his "mojo" a disheartening experience, and Yang searches high and low for a missing appendage.
Addison and Derek go to marriage counseling. Derek says that he's finished with Meredith. Meanwhile, Meredith becomes the main gossip topic in the hospital and Izzie and Christina discover a pregnant man. Preston tells the Chief about him and Christina and Alex finally kisses Izzie.
Thanksgiving sends the occupants of the house in different directions: Meredith escapes to the hospital, George goes hunting with his family, and Izzie throws a dinner that it appears no one is coming to.
Meredith's one night stand causes complications when he shows up at the hospital with an embarrassing problem, Burke tries to push Cristina toward the next step, and Alex's problems affect his performance.
Izzie realizes that she is attracted to her patient with a heart condition. George treats Bex, a hermaphrodite. Meredith's mother gets a special visitors. Derek and Addison's relationship is still rocky.
The nurses strike, leaving the doctors unprepared for their extra duties. Cristina and Burke have to define their work relationship, Izzie relates to a pregnant teenager, and Meredith finds parallels to her mother in a case requiring her to remove life support.
George begins to overstay his welcome at Burke and Cristina's apartment. Cristina takes a seminar and discovers that Chief Webber is taking it too. Meanwhile, Meredith learns a startling secret about her father, Bailey worries her colleagues will not treat her the same now that she's a mother, and Alex gets a lesson in bedside manners.
While Izzie grills George about the personal details of his life, Addison takes Alex to task about a sensitive case. Also, Burke feels the pressure when he treats his musical hero, and Meredith considers dating a hunky vet.