In the aftermath of Izzie's affair with George, he doesn't seem to remember anything. Callie lets him know that they will be having dinner with her father, but George does not make a good impression, being hung over after last night's events. Alex helps Jane Doe choose how her face will look like after Mark Sloan performs reconstructive surgery on her. He also gives her a new perspective on how the world will see her from then on. The hospital board begins interviewing the candidates for the Chief's position, and Colin Marlow intimidates everyone with his ten-year plan. However, after taking advice from Bailey, Mark seems to have convinced the board that he is appropriate for the job, despite continuous efforts from Derek, Burke and Addison, whose careers in the hospital outlast his. Izzie seeks advice from Addison about her affair, telling her sleeping with George felt right, despite him being married. Mark takes Meredith as his intern for the day in order to impress the Chief, something that Derek doesn't approve of, feeling that Mark has become manipulative.

Colin Marlow continues to try to get in the way of Cristina and Burke's relationship. The daughter that Izzie gave up for adoption needs something from her. This episode features a pro chess player, a flirtatious woman, and a mother named Mrs. Malone. Mr. and Mrs. Malone haven't talked to their daugther in a while because of their son-in-law. Someone goes to see a priest.

The attendings vie to be Chief. Two people who haven't slept together before, will. McSteamy's 60-day vow of chastity has a conclusion. We meet a boss, his assistant, and his wife. We also get to see someone being treated in the clinic. Derek has more questions about his relationship with Meredith. The chairman of the hospital board is admitted as patient. Callie confronts Izzie about her relationship with George.

Meredith works on her relationship with Susan and Thatcher. Cristina has to deal with her mother and Burke's. Alex continues to tend to Jane Doe/Ava. Meredith and Derek's relationship has a problem that needs resolution quick. Addison sees her god-daughter which leads to a job offer outside of Seattle. Derek has to perform surgery. Burke has a reservation about marrying Cristina. Many new people guest star in the course of Addison's road trip to California. Addison considers moving to be closer to her old med school friends until she discovers that drama she wishes to leave behind isn't exclusive to Seattle. Her friends who she thought had it all, are divorced. A pregnant woman must discover who the father of her child is.

Meredith works on her relationship with Susan and Thatcher. Cristina has to deal with her mother and Burke's. Alex continues to tend to Jane Doe/Ava. Meredith and Derek's relationship has a problem that needs resolution quick. Addison sees her god-daughter which leads to a job offer outside of Seattle. Derek has to perform surgery. Burke has a reservation about marrying Cristina. Many new people guest star in the course of Addison's road trip to California. Addison considers moving to be closer to her old med school friends until she discovers that drama she wishes to leave behind isn't exclusive to Seattle. Her friends who she thought had it all, are divorced. A pregnant woman must discover who the father of her child is.

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.