Meet Meredith Grey. Daughter of famous surgeon Ellis Grey and currently recovering from a one-night stand. She shoos away her evening's companion, saying she'll be late for her first day of work. She is a first year intern at Seattle Grace Hospital and is working alongside some colorful characters. Cristina Yang is a highly competitive Stanford graduate who befriends Meredith. George O'Malley is a quirky warm hearted man who learns a lesson or two on his first day. Izzie Stevens is a former model who doesn't get any special treatment on her first day. And Alex Karev is an arrogant jerk who misdiagnoses a patient on his first shift. Overseeing them is Miranda Bailey, (not-so-) affectionately dubbed 'The Nazi'. Meredith also gets a surprise when she realizes that her friend from the night before is a co-worker, and even worse, her boss.

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; while taking on the responsibility of an object that she wished she never had to look after. The other interns learn that it takes more than just medical knowledge to be good at their jobs.

When a bike race leaves one pedestrian brain dead, interns Cristina and Izzie face an emotional crisis of conscience: how long does one wait before they start harvesting his organs? Cristina is all detached professionalism , but ever-hopeful Izzie prays for a miracle. Meanwhile, George avoids a flirtatious patient while Meredith copes with living with roommates and tries to dodge Derek's ever-increasing advances.

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 lose 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 participates in her first heart surgery. During the surgery, she fears that she has damaged the patient's heart and is unsure of whether or not she should speak up, because she could get kicked out of the program. Meanwhile, Cristina and Burke share some comments over coffee. At the party, Meredith and Derek do some sneaking.

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.