Izzie tries to get George to find the courage to ask Meredith out. All of the interns are in awe when a woman comes in with a record breaking tumor, but it is so far advanced that the woman's prognosis is not good. Now that Bailey knows about Meredith and Derek's affair, their jobs are in jeopardy, and she advises Meredith to end it. Meanwhile, Cristina and Burke's secret relationship is also getting more complicated...

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.

Cristina gets to scrub in on a rare surgery which incites envy. Alex questions his future in plastics. George and Addison work together with Noelle. Noelle is pregnant with twins but one of them is growing slower than the other. Her fiancé has problems of his own. Derek's sister visits. A patient's wife makes things hard on the staff since she has made her husband's health her job. A woman's sexual exploits are questioned.

Cristina and Burke continue to play Uncle until one of them gives in. Derek and Meredith are fighting over the reason for their sleepless nights. Meredith tries to talk to her father about his side of the story. There's tension between Alex and Addison. There is even more tension between Addison and Mark. Addison confides in Callie. Bailey wishes she didn't have to keep a secret from one of the interns. Callie rushes to be with George after she learns that his dad needs an emergency procedure. Izzie may have found 'some good to do' with her inheritance.

Meredith works furiously to save a paramedic trapped in an ambulance; Lexie holds the life of a patient in her hands; Derek must rely on a nurse to save a patient; Bailey struggles to balance her personal life with her work.

Catherine is in Los Angeles getting the new foundation ready and summons Meredith and Koracick to visit for a highly confidential consult. Meanwhile, one of the nurses is 28 weeks pregnant and collapses at the hospital while talking to Richard.