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.

The interns finally take their first year medical exams, the biggest test of their careers, and one of them is ill-prepared. Callie grows more suspicious of George and Izzie. The doctors treat a patient named Dale. Three mountain climbers are treated. Cristina works on her vows. Adele wants Addison to keep a secret from Richard.

The mountain climbers lie about the axe in their friend's head, telling Derek that it accidentally got there. During surgery, he and George discover that it was deliberately put there, and one of the climbers admit that he was trying to "put him out of his misery". Adele is saved after Richard finds her lying in the bathroom and is stabilized, but soon suffers a miscarriage. Richard learns Adele was actually pregnant with his son, not someone she had one night stand with. Bailey is disappointed to see that Callie is the new Chief Resident and begins to question her abilities as a surgeon. Richard chooses Derek as Chief of Surgery, but he refuses, telling him that he isn't done doing what he does best. Cristina and Burke's wedding day arrives, but Cristina won't stay out of the hospital. However, Cristina's nervousness results in Burke's realizing that he does not love the real Cristina and leaves her. Meredith and Derek are uncertain about their future and despite Derek admitting that she is the love of his life, they call their relationship over.