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.

George and Derek work together, Denny still doesn't have a heart, and Meredith gets paired with Callie. A 12-week pregnant girl dies in the O.R. and her parents try to keep the baby alive. This causes tension between Derek and Addison. One doctor's overreaction unites two bickering patients. Finn is still treating Doc for medical problems.

The men of Seattle Grace go on a camping trip together, Addison and Callie must team up to work on a patient, Meredith assists Sloan with a procedure unlike any she has experienced, and, suspicious of her recent actions at the hospital, Bailey confronts Cristina. A 9-year-old is seen by Cristina after he swallowed Monopoly game pieces. A pregnant 25-year-old, is brought in after she slipped in the shower. She doesn't want medicine to take away the pain from her injury so not to put her baby's growth in jeopardy. Doctors take care of Daniel, a man who wants a sexual reassignment surgery and who now goes under the name Donna. Accompanying Daniel is his wife of the past 10 years, who was surprised to see him want that surgery but, after much struggling, decided to stay by his side.

The attendings vie to be Chief. Two people who haven't slept together before, will. McSteamy's 60-day vow of chastity has a conclusion. We meet a boss, his assistant, and his wife. We also get to see someone being treated in the clinic. Derek has more questions about his relationship with Meredith. The chairman of the hospital board is admitted as patient. Callie confronts Izzie about her relationship with George.

The doctors meet the world's oldest intern. Marcy brings in her son Henry because she finds his change in behavior suspicious. A patient named Connie may lose her vocal chords unless Mark and Richard can perform a radical new surgery. George impresses the other interns at work but at home he is trying to deal with his guilt about having sex with Izzie.

There has been a bus crash and the patients are in the ER. Meredith and Derek's relationship gets more complicated when he dates a fellow doctor. Meredith's dad goes to visit her at the hospital.

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.

Bailey grows desperate as a patient's condition becomes more and more dire. Everyone in the hospital is stepping up to try to find the boy a new organ donor, including Meredith, who considers a death row patient's wish to die before execution. Meanwhile, an injury leaves Mark in a compromising position in the OR and Cristina awkwardly avoids Owen.

The residents of Seattle Grace and Mercy West vie for surgeries and their careers as day one of the hospital merger begins. Meanwhile, Arizona stands by an enraged Callie when her father, Mr. Torres, employs a priest to help convince her to date men, and Izzie experiences the brunt of her new surgical competition.

Issues surface when Derek's estranged sister, Amelia (Caterina Scorsone), visits unexpectedly; Meredith and Derek continue to try to ease Cristina back into surgery.

Derek breaks ground on his Alzheimer's clinical trial and Meredith can't help but feel left out; Bailey's attempt to take the hospital into the age of new media with live tweets from the OR does not go over well with the Chief; and Callie, Mark and Arizona must learn to navigate through the pregnancy together, which starts off with Callie driving her new obstetrician crazy.

The residents determine their future as they make their final decisions regarding post residency positions; Mark admits to Derek that he is torn between his love for Lexie and the fact that Julia can give him everything he's ever wanted; Ben plans something extra special for Bailey, but she is preoccupied with her work; and Arizona encourages her childhood friend, Nick, to have surgery. Meanwhile a couple on their third honeymoon come to the hospital complaining of mysterious symptoms.