Train Wreck victims come to Seattle Grace and all staff gets called in. Everyone deals with really weird cases. Except Addison and Izzie. They work with a woman who is pregnant.

Cristina Yang has little sympathy for Constance Ferguson (special guest star Rosanna Arquette), a prison inmate who jeopardizes her health just to get out of solitary confinement. Meanwhile the interns all keep careful watch on the family of premature quintuplets with a variety of serious health challenges, Izzie's anger at Alex reaches boiling point, and Dr. Addison Shepherd decides to teach Izzie a very painful lesson.

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.

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.

Cristina meets Burke's parents, the interns try to get Izzie's job back, and Addison takes a day off, a surgical patient may be living her last day. Some of the interns want to know why Bailey won't talk to Izzie. Meredith tries to decide between Derek and Finn and comes to a decision somewhat. Webber finds out that Callie has been living in the hospital and he confronts her about it.

A patient is in the hospital because they fell asleep in a hazardous situation. A patient's home laboratory blew up in an apartment building and the victims flood the hospital. Alex investigates the cause of the incident by talking to a really old guy who lived in the building. Jane Burke shows up to deal with what her son left behind. Lexie tries to talk to Meredith. Callie is overwhelmed by her new position while Bailey is searching for things to do.

The chief gives Bailey new power and responsibility. He also gives her a very difficult surgical assignment: remove a girl's inoperable tumor. Meanwhile, new trauma chief Owen (Kevin McKidd) challenges the attendings' methods and the residents' skills.

As preparations continue for Meredith and Derek's wedding, Izzie receives a surprise hospital visit from her handful-of-a-mother, Robbie. Meanwhile, a newly sober Thatcher visits his daughters, Meredith and Lexie, in order to make amends, and the Chief and Meredith bitterly fight over a controversial medical case.

In the second part of the two hour season finale, George delivers stunning news to Bailey, sending shockwaves throughout the hospital, and Izzie's friends anxiously await her recovery from surgery. Meanwhile Bailey is surprisingly displeased after being accepted into the pediatric fellowship program, and the victim of a near-fatal traffic accident brings the talents of Seattle Grace's doctors together. This is the second hour of a 2-hour season finale.

When Alex's younger brother, Aaron, shows up at Seattle Grace-Mercy West with a hernia, it's up to Alex to get Bailey's approval for his pro bono surgery. Matters are further complicated when Aaron discloses that his family has not heard from Alex since he arrived in Seattle, and parts of Alex's past long kept secret are revealed to his friends and fellow doctors.

A gunman opens fire at a local college, sending mass casualties to the hospital; Arizona's return is not warmly received.