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.

Meredith tries to avoid the Shepherds. Cristina and Burke go out on a date and end up getting caught up in their jobs. Derek asks Meredith not to ignore him until Addison comes walking around the corner.

Derek and Addison's relationship is rocked to the core when a former friend comes to Seattle Grace and his presence promises to shake things up for a few members of the staff. Burke and Cristina's relationship is affected when one of her secrets is outted. Alex and Izzie are having similar reactions to their closet scenes during the Code Black crisis. On top of this a cocky doctor shows up to piss Derek off in all kinds of ways. A patient is suffering from constant orgasms and her condition sparks interesting conversations among the staff. George is trying to figure out how to get Meredith to see him as more than just a housemate. Another patient, that Derek is treating, is dealing with a rare disorder and needs his parents support and understanding. Burke has a patient who inspires him to talk to Meredith and Cristina about doing what they say they will. Meanwhile, Meredith learns more about her family (in fact maybe more than she may have wanted to know) through her parents.

The staff attends to an intern from another hospital who has short-term memory loss. This intern, named Marshall, also has caused a car accident that involved a married couple, their unborn baby and the woman's parents who the staff are also treating. The pregnant woman is named Melanie and she will die but her baby may survive. One of the female interns meets up with a woman from her past who is planning on having a family of her own. Cristina is in a good mood although Alex, Izzie, George, and Meredith are having problems but in the meantime Burke hasn't forgiven Cristina for her late night faux pas. Meredith and Izzie are making fun of Callie's household habits and George and Callie are having a fight because of George's roommates. Addison is continuing to own Alex and he's upset about it. Denny has an outburst at Izzie and Derek has an outburst at Meredith.