After a series of deaths at the hospital some of the staff become very superstitious. Izzie worries about Denny and gets confronted by Alex. A patient with OCD drives Cristina crazy. Derek and Addison discuss their relationships with Meredith. Richard treats a friend from 17 years ago who reveals a secret about a dark time in his past that involves Ellis. George gets an earful about the women he's not talking to. Burke and Cristina argue about kicking George out.

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.

Meredith must make an important choice about which path she wants to follow to determine the future of her love life. While she considers her future she and others have flashbacks of their pasts. Cristina spends time with Burke while he recovers. Webber and Adele have a conversation after he spends the night at the hospital. Everyone attempts to deal with Izzie's choice to quit. George seeks relationship advice from Derek.

As Meredith, Derek and all of their friends prepare for the big wedding, a group of college students, injured in a car crash as they were heading to their graduation ceremony, is admitted to the ER. Meanwhile, Izzie fears the worst when she begins experiencing familiar symptoms.

A small plane crash in Seattle causes multiple casualties and brings back horrible memories for the doctors, especially Meredith and Arizona. Meanwhile, friction between Owen and Amelia makes for an uncomfortable working situation for Stephanie.