The mountain climbers lie about the axe in their friend's head, telling Derek that it accidentally got there. During surgery, he and George discover that it was deliberately put there, and one of the climbers admit that he was trying to "put him out of his misery". Adele is saved after Richard finds her lying in the bathroom and is stabilized, but soon suffers a miscarriage. Richard learns Adele was actually pregnant with his son, not someone she had one night stand with. Bailey is disappointed to see that Callie is the new Chief Resident and begins to question her abilities as a surgeon. Richard chooses Derek as Chief of Surgery, but he refuses, telling him that he isn't done doing what he does best. Cristina and Burke's wedding day arrives, but Cristina won't stay out of the hospital. However, Cristina's nervousness results in Burke's realizing that he does not love the real Cristina and leaves her. Meredith and Derek are uncertain about their future and despite Derek admitting that she is the love of his life, they call their relationship over.

Entering their first year as residents, Meredith Grey, Cristina Yang, Izzie Stevens and Alex Karev now have interns of their own to mentor. Among the new interns are George, forced to repeat his internship after failing his exams, and Lexie Grey, Meredith's half-sister. Another two new interns will be introduced in this season premiere. And they'll have their hands full when a three-car accident sends multiple casualties pouring into Seattle Grace. Some of the doctors need to deal with new stressed out interns. A young boy brings his bleeding deer to the hospital in the hope a doctor will save her.

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 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.

An ambulance crash endangers the lives of the paramedics involved, as Meredith and the Chief work on-site to save them, Bailey treats a patient who refuses her help, and Ava returns for Alex and meets his other girlfriend in the process.

The clinical trial continues to make progress. The anti-McSteamy club creates new initiatives but that isn't enough to stop one woman from spending time with him. Christina is affected by Burke's career developments.

When the plumbing springs a leak, chaos breaks out at Seattle Grace as the Chief tries to put in place new teaching methods. Meanwhile, George takes his residency exam; and Derek attempts to get Meredith's roommates to move out, much to their surprise.

Meredith is sent into a state of panic when Derek finds her mother's diary in the house. Meanwhile, Callie stresses while preparing for her first date with Erica. Later, Cristina stumbles across a part of the hospital no one has ever seen before.

Bailey heads up a "domino procedure" in which each surgery hinges on the one preceding it. Meanwhile, Derek gets sole credit for the brain-tumor study he did with Meredith; Lexie tries to get George to notice her romantically; and Sloan counsels a desperate Callie in the ways of love.

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 teams with Seattle Grace's new pediatric surgeon, Dr. Arizona Robbins, to save the life of a young patient near and dear to her heart, as the admittance of a death row inmate at the hospital stirs anger in Derek and further erodes Meredith and Cristina's friendship; meanwhile, Callie and Sloan work as a team to fight their respective attractions to Sadie and Lexie, and Izzie tells Alex that she's seeing Denny.

Derek's mother, Carolyn, makes a surprise visit to Seattle and meets Meredith for the first time, as Mark tries to conceal his relationship with Lexie from her as well; meanwhile, death row inmate William wishes to donate his organs to Bailey and Arizona's patient, as Owen and Cristina try to go on their first date.

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.

Addison, Naomi and Sam rush the ailing Archer to Seattle Grace and reunite with old friends Derek and Mark to help save his life; meanwhile, Izzie employs her fellow doctors in a medical game designed to help teach the interns, and Owen runs into a significant someone from his past

Derek decides to quit after learning that more of his patients have died than survived; Izzie's interns make an unsettling discovery about "Patient X."

After his fellow surgeons try and fail to bring Derek back to work, Meredith must summon the strength to convince him. Meanwhile the hospital is abuzz as Mark attempts a rare face transplant surgery. Cristina, at last awarded her first solo surgery, is more focused on the needs of her friends, and Izzie does her best to keep her medical condition a secret.

All eyes are on Derek as he is set to perform his first surgery after his breakdown; attention is also set on Izzie, whose medical condition requires her to undergo a difficult surgery; and Owen has another PTSD episode that injures Cristina and traumatizes both of them, throwing the future of their relationship into question.

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.

Several weeks after her near-death experience, a recovering Izzie returns to work. Meanwhile, nervous that there will be layoffs in the hospital in the wake of an announcement from the Chief, the Seattle Grace residents compete to survive the cuts, including Cristina, who attempts to work alongside Arizona in pediatrics. And Bailey and Alex's patient's already complex case is further complicated by her schizophrenic son.