The surgical staff tries to be optimistic as a young woman clings to life after a brutal attack. Meanwhile Meredith puts her career on the line to save a newborn in the hospital nursery, and the other interns learn that it takes more than just medical knowledge to be good at their jobs.

A sexually transmitted disease breaks out and affects several members of the hospital staff. Chief Webber promptly calls a meeting. Meanwhile, the chief reluctantly tells Dr. Derek Shepherd about his own medical concerns. Izzie and Cristina worry about a patient's wife and daughter who can't agree on his care. Burke treats his college buddy Bill, whose medical diagnosis raises some questions regarding his wife's actions. Then just as Meredith and Derek grow more intimate, a surprise is revealed.

Picks up where the last episode left off. Meredith attempts to work with Addison Shepard. George is pimped out to relay the hospital gossip back to Webber. Meredith and Cristina relate at Emerald City Bar about what dating their respective attendings is like. Cristina ponders her relationship with Burke while trying to make a decision. Meredith is devastated by the latest blow to her love life. Meanwhile, Joe the bartender collapses.

There's tension between Meredith and Addison. We find out why Derek and Addison aren't together. Bailey puts George on an impossible case. The rest of the interns operate on a family that was just in a car accident.

Train Wreck victims come to Seattle Grace and all staff gets called in. Everyone deals with really weird cases. Except Addison and Izzie. They work with a woman who is pregnant.

Dorie Russell is waiting for quintuplets, all 5 girls. Her husband seems more concerned than she is but she is set to bring her babies to their term of 36 weeks. All the departments are on call for the quintuplets as three of them have developped problems of different kinds. Meredith last night's stand shows up at the hospital with priapism and they need to call Derek Sheperd for a consult which puts Meredith in a very embarassing position. Alex and Derek must take care of a patient who has a tumor inducing thirst as a side effect. On the love side, Alex and Izzie are having some slight sexual problems, while Meredith goes on adding one night stands and Cristina is thrown off course by being "keyed."

The holiday season has started but not everyone is in a festive mood. This is Alex's last day in the hospital unless he passes his boards practical exam the next day, thus everyone helps him to review so that he succeeds. However, Izzie is not happy about the others helping him and Meredith has to remind her of the true spirit of the Christmas holiday. Justin is in need of a new heart. One is available but he does not want it because he does not believe Santa gave it to him as his mother said. Cristina and Burke, both handling Justin's case, have opposing views on the matter due to their different stances on religion. Despite a reconciliation with his wife, Derek isn't in a festive mood. George has a simple case of a woman who has a bleeding ulcer, he realizes that the ulcer is caused by her entourage but fails to keep them away, with the consequence that it perforates.

Meredith and Cristina lie to each other and themselves about their relationships with McDreamy and Burke, respectively. George is given a hard task to expel a discharged and defiant woman from the hospital. Alex learns his fate after re-taking his medical exams. At the same time Izzie is trying to stop Alex from making stupid decisions when a patient that doesn't speak English is lied to by her coach. George, Cristina, and Alex compete in a hot dog eating competition.

All the nurses at Seattle Grace Hospital go on strike, leaving the doctors to fend for themselves. George refuses to cross the picket line and finally joins the nurses on their strike while Alex, Cristina, Izzie and Meredith meets Bailey's stand-in: Dr. Cindy Aaron, the complete opposite of Miranda Bailey. Izzie agrees to work on a difficult pregnancy case with Addison, while Cristina and Alex are in the pit attending to a young married woman with a real bad case of rash. Meredith happens on an old woman that she needs to intubate and then learns she was DNR.

George and Derek work together, Denny still doesn't have a heart, and Meredith gets paired with Callie. A 12-week pregnant girl dies in the O.R. and her parents try to keep the baby alive. This causes tension between Derek and Addison. One doctor's overreaction unites two bickering patients. Finn is still treating Doc for medical problems.

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.

Bailey teams with Seattle Grace's new pediatric surgeon, Dr. Arizona Robbins, to save the life of a young patient near and dear to her heart, as the admittance of a death row inmate at the hospital stirs anger in Derek and further erodes Meredith and Cristina's friendship; meanwhile, Callie and Sloan work as a team to fight their respective attractions to Sadie and Lexie, and Izzie tells Alex that she's seeing Denny.