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.

Entering their first year as residents, Meredith Grey, Cristina Yang, Izzie Stevens and Alex Karev now have interns of their own to mentor. Among the new interns are George, forced to repeat his internship after failing his exams, and Lexie Grey, Meredith's half-sister. Another two new interns will be introduced in this season premiere. And they'll have their hands full when a three-car accident sends multiple casualties pouring into Seattle Grace. Some of the doctors need to deal with new stressed out interns. A young boy brings his bleeding deer to the hospital in the hope a doctor will save her.

As Meredith and Derek begin to find that their "happily ever after" is anything but easy, Cristina develops a crush on a military doctor who brings in a trauma patient. Meanwhile, the Chief and his staff cope with the news that Seattle Grace is no longer considered a top-tier teaching hospital.