It's Thanksgiving at Seattle Grace Hospital but the holiday's festivites are less than in order. Meredith and Derek try to counsel a family after their relative has had a seriously traumatic accident.

The men of Seattle Grace go on a camping trip together, Addison and Callie must team up to work on a patient, Meredith assists Sloan with a procedure unlike any she has experienced, and, suspicious of her recent actions at the hospital, Bailey confronts Cristina. A 9-year-old is seen by Cristina after he swallowed Monopoly game pieces. A pregnant 25-year-old, is brought in after she slipped in the shower. She doesn't want medicine to take away the pain from her injury so not to put her baby's growth in jeopardy. Doctors take care of Daniel, a man who wants a sexual reassignment surgery and who now goes under the name Donna. Accompanying Daniel is his wife of the past 10 years, who was surprised to see him want that surgery but, after much struggling, decided to stay by his side.

George's father has a serious heart problem that requires surgery and George chooses Burke to do the procedure. Burke doubts himself because he knows the pressure this kind of surgery will put on him, but Cristina believes the team can handle it. Derek works with Meredith on being a couple again and tries work with Addison on more civil terms. A patient has had mutiple plastic surgeries so that his girlfriend will like him more. A mom wants her daughter's babysitter fired, after she is brought in with multiple injuries, but the girl likes the babysitter more than her mother.

A traumatic car accident fills the ER. Izzie pushes the boundaries of her probation. Cristina has a crisis of conscience about her deceptive teamwork with Burke.

Recent events strain Burke and Cristina's relationship. Mark and Derek must work together when two close-knit brothers seek medical help. One of Meredith's half sisters is admitted to the hospital.

Meredith discovers that Derek has a problem sleeping while her father comes to visit the hospital. George's father is moving from one surgery to another. A patient named Heather checks into the hospital. Heather is 17 and has a nasty attitude that results from her medical condition and all the surgeries it has required her to have. Izzie has an emotional breakdown when she tries to hand over something very important to her. George's family comes to visit to celebrate his father's surgery. Cristina and Burke are playing Uncle.

Cristina and Burke continue to play Uncle until one of them gives in. Derek and Meredith are fighting over the reason for their sleepless nights. Meredith tries to talk to her father about his side of the story. There's tension between Alex and Addison. There is even more tension between Addison and Mark. Addison confides in Callie. Bailey wishes she didn't have to keep a secret from one of the interns. Callie rushes to be with George after she learns that his dad needs an emergency procedure. Izzie may have found 'some good to do' with her inheritance.