The doctors are up to their necks in their usual levels of drama. Meredith is dealing with the backlash of sleeping with George, George and Burke are bonding in ways that bother and creep out Cristina, Cristina gets stuck on diaper duty, Bailey gets involved in a case even though she's still supposed to be on maternity leave, Addison and Derek have a talk, and Izzie is still flaking on Alex for Denny Duquette, the heart patient who didn't get a heart. In the patients-of-the-week department we've got a very pregnant woman, a hockey player who desires medically unnessasary amputation, and a woman with a fork in her neck who happens to be dying and has a struggling marriage.

A traumatic car accident fills the ER. Izzie pushes the boundaries of her probation. Cristina has a crisis of conscience about her deceptive teamwork with Burke.

The race for the Chief's position is on, and the attending physicians, Derek, Burke, Addison and Mark, compete for Richard's affections by trying to help out everywhere possible. The Denny Duquette Memorial Clinic is open for business, but only one single patient shows up. Izzie is disappointed in what she invested Denny's legacy in, and tries to steal patients from the emergency room. Callie and George get back from Las Vegas, announcing their marriage, much to everyone's disbelief. Izzie is not supportive of their marriage and tries to get George to realize the mistake he has made. Meanwhile, Meredith's Alzheimer's-stricken mother, Ellis Grey, experiences a change in her medical condition by becoming lucid for the day. She is disappointed in the mediocrity her daughter has fallen into and begins to despise Derek, blaming him for what happened to the Meredith that used to be "a force of nature". Ellis has to have heart surgery and, despite her wishes, Meredith schedules her upcoming surgery. Richard talks to Ellis and realizes that she is still in love with him, but loses her memory after their talk ends, before Meredith has the chance to tell her how she really feels.

The clinical trial continues to make progress. The anti-McSteamy club creates new initiatives but that isn't enough to stop one woman from spending time with him. Christina is affected by Burke's career developments.

Now that Derek has the engagement ring, he searches for the perfect way to propose to Meredith, as Lexie demands that Mark go public with their relationship, and Bailey, encouraged by her work on recent cases and by Dr. Dixon, considers a new direction for her medical career.