A mass trauma situation, which turns out to be a ferryboat accident, challenges the whole staff of Seattle Grace Hospital. Richard finds difficulty in coping with his separation from his wife and dyes his hair "for the ladies", which becomes an internal joke between Mark, Burke and Derek. Cristina tries to tell Meredith about her upcoming marriage, but doesn't have the strength to. George promises to find a woman's son, who has been separated from her at the accident. The woman refuses to go into surgery until she is assured that her son is alive. Izzie has to take care of a man who got stuck between two cars on the ferry, but nobody helps her due to the large number of injured people. Alex rescues a pregnant woman with severe wounds on her face, and promises to take care of her. Meredith looks after a girl who has been separated from her mother after the accident, but accidentally falls into the water and drowns, with nobody but the little girl as a witness.

Meredith is still underwater, but nobody seems to notice. Her worsening condition makes her rescuing an urgent matter. Derek finds her coat on a man she had helped, and starts looking for her and, much to his shock, the little girl Meredith took care of suggests that she is in the water. Derek saves her, but she is almost dead, due to hypothermia. Izzie has to perform brain surgery on a man stuck between cars, as he begins to experience seizures. She drills holes into his head, perforates his skull and ultimately saves his life before he is rescued and transferred to Seattle Grace Hospital. George lies to the woman whose son he had been looking for, in order to get to surgery, but still doesn't have any luck in locating him. Alex finds no hope in searching for the pregnant Jane Doe's family as she undergoes surgery. The interns find out about Meredith's situation and express their hopelessness. She wakes up in what appears to be limbo and meets her deceased acquaintances.

Everyone is pushing for Meredith to survive, or in this case to be revived. People are still dealing with the fallout from the ferry disaster. A young man named Lucas is having problems with brain-mouth coordination. Someone else dies.

The race between the attending physicians for the Chief of Surgery position heats up after a new competitor enters the fray. They soon realize that the new surgeon, Colin Marlow, was Cristina's professor in medical school and they used to have a long-term relationship. He begins to lie to Burke in order to protect her secret, but is soon faced with the realization that their relationship is on the rocks. George finds out that Callie's family is rich, but she had previously hidden the fact in order to find out whether George loves her for who she really is. Derek treats his former colleague from New York, and forces her to have surgery for brain cancer in order to save her future, no matter what the post-surgery risks are. Alex continues to work with Jane Doe, whose memory doesn't seem to come back. He moves in with Meredith and they have a dinner with her father and stepmother. She seems to connect with Susan, but her relationship with Thatcher seems to be irreparable. Izzie wakes up, realizing that she has slept with George while they were both drunk.

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.