A bike race injures several pedestrians as well as well as participants. One pedestrian is left brain dead. Christina and Issie wish to use his organs for organ donation but with Christina's detachment and Issie's ever hopeful attitude that the man will recover, they will find the organ harvesting process an emotional one. Preston faces feelings of his dislike of organ harvesting - as a surgeon, he likes saving lives; harvesting organs doesn't save the person's life. George deals with Mac, a friend of the chief, who won't stop flirting with him. He is in need of a new liver. Meredith is fed up with Alex showing off as she continues trying to push Derek away. She also is reaching the limits of Issie's sunshine and George's politeness as she goes on living with them. Then there is their desire to see Meredith's mother's medical tapes. Getting through the day, Meredith realizes the keys to winning the race.

While George is feeling a little less masculine because of the way Izzie and Meredith have been treating him (like a sister), Izzie is assigned to a patient about to loose all of his masculinity. Cristina, true to her competitive spirit, shows up early and assigns herself to an ill woman, who happens to have been Meredith's moms scrub nurse. Alex, meanwhile, is busying himself copying and pasting pictures of Izzie's racy magazine spread all over the interns' locker room. And while Meredith is trying to cope with her mother's Alzheimer's, Derek treats a patient who has managed to get nails stuck in his head.

Meredith realizes that she must take on a lot more responsibility when she is told that her mother needs to sign over all of her assets to her. As Izzie prepares to have a party for her boyfriend Hank (the scale of which is unknown to Meredith), Meredith has her first heart surgery. During the surgery she fears that she has fallen asleep and damaged the patient's heart. Meanwhile, Cristina and Burke hit it off. At the party, Meredith and Derek get caught together by Dr. Bailey.

Izzie tries to get George to find the courage to ask Meredith out. All of the interns are in awe when a woman comes in with a record breaking tumor, but it is so far advanced that the woman's prognosis is not good. Now that Bailey knows about Meredith and Derek's affair, their jobs are in jeopardy, and she advises Meredith to end it. Meanwhile, Cristina and Burke's secret relationship is also getting more complicated...

Derek and Meredith try (unsuccessfully) to be discreet as they spend the night together at Meredith's house, but their haggard appearance speaks volumes to everyone - including Bailey, who warns Meredith to end the relationship. Meanwhile George suspects an anesthesiologist of drinking on the job but is reluctant to speak up about it, Alex treats a former competitor who now finds honor in self-mutilation, Izzie has to deal with a patient who won't let go of his girlfriend - literally, and Cristina seems to be battling a case of the flu.

Meredith grows increasingly dissatisfied with the unknown details of Derek's life. Meanwhile, Alex treats Devo, a patient whose religious beliefs jeopardize her chances for recovery; Izzie contemplates reconnecting with her estranged mother; Zoey, a pregnant woman in her 40s who's been diagnosed with cancer, disagrees with Cristina's medical advice; and the interns are mystified by Cable, a patient who's being treated for seizures and who thinks he's psychic.

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.