On the morning of her first day as a surgical intern at Seattle Grace Hospital, Meredith Grey is running late as she recovers from a one-night stand and prepares for her first day. Meredith quickly befriends George O'Malley, who's quirky, yet lovable, Cristina Yang, a highly competitive woman, and Izzie Stevens, a model turned surgical intern. Each of the new interns get assigned to Dr. Miranda Bailey, who past interns have dubbed the Nazi. Meredith's first patient, a young beauty pageant contestant, recently began having severe, life-threatening seizures and Meredith uncovers that she'll need brain surgery to save her life. However, things take a turn when the neurosurgeon, Dr. Derek Shepard, happens to be Meredith's one-night stand. He wants their brief relationship to progress into something more, but Meredith is firm on her stance - their relationship should remain strictly professional.

The surgical staff tries to stay positive when a young woman, despite brain surgery, is clinging to life after a brutal attempted rape. Meanwhile, Meredith risks her spot in the intern program when she crosses the line in order to save a newborn suffering from a undiagnosed heart condition. The other interns learn that in order to be a good surgeon and doctor, much more than medial knowledge is needed.

On the day of a bike race, injured individuals flood into the hospital, including a pedestrian who is left brain dead. Seeing that he has no chance of ever waking up, Cristina and Izzie wish to use his organs for organ donation, but find that the process is an emotional one. George gets assigned to Mack, a good friend of Chief Webber, and constantly flirts with George. Meanwhile, Meredith continues to try to distance herself from Derek and is forced to deal with Alex's big ego, but through the day, Meredith begins to realize the key to winning the battle.

While George begins to feel that he's loosing his masculinity due to Izzie and Meredith treating him like a sister, Izzie's newest patient may loose his masculinity to prostate cancer. Cristina assigns herself to a sick woman, who she believes will need surgery, but ends up learning more from the woman then standing in on a surgery would ever give her. Meredith faces the reality of her mother's Alzheimer's when Derek treats a patient with nails in his brain. Meanwhile, Alex tapes up pictures of Izzie's racy spread all over the locker room.

Meredith realizes the responsibility of adulthood when her mother has to sign all of her assets over to her. Izzie decides to throw a party for her boyfriend, Hank, and the scale of the party, which Meredith is unaware of, increases throughout the day. After popping a glove during a heart surgery, Meredith fears that she damaged the patient's heart and has to face a meeting with the chief and lawyers who will determine her future as a doctor. Meanwhile, sparks start to fly between Cristina and Burke, and Meredith and Derek's relationship is exposed when Bailey catches them together at the party.

The interns are speechless when a woman comes in with a large, record-breaking tumor, but unfortunately for the woman, her outlook isn't good. Derek and Meredith's jobs are at risk now that Bailey knows about their relationship, and Dr. Bailey makes it clear that Derek better not give Meredith special treatment. Meanwhile, Izzie urges George to ask Meredith out, and Cristina and Burke's relationship continues to progress.

Derek and Meredith try to spend a night together at Meredith's, but their appearance the next morning does more harm than they expected and leads Bailey to tell Meredith to end it. Alex treats a self-mutilation patient, while Izzie's patient literally won't let go of his girlfriend. Meanwhile, George is suspicious that an anesthesiologist is drinking on the job and Cristina fills ill with flu-like symptoms.

The interns treat a patient who, after a series of seizures, thinks he's gained psychic abilities. Meredith becomes dissatisfied with her relationship with Derek when she realizes that she knows nothing about his personal life. Alex treats a patient whose religion interferes with her recovery; Izzie debates whether or not to reconnect with her mother; and Cristina's patient disagrees with her medical advice.

When an STD breaks out, affecting several members of the staff, Webber calls a staff meeting. Later, the chief confides in Derek about his own medical concerns. Izzie and Cristina become stressed when a patient's wife and daughter can't decide on his care. Burke treats an old college friend, Bill, but his diagnosis creates questions about his wife. As Meredith and Derek continue to get closer, their relationship crashes down around them when a person from Derek's past shows up in his life.