Having just returned from her honeymoon with Meredith, Cristina searches for Burke, but he's nowhere to be found. Meredith, Cristina, Izzie and Alex spend their first day as residents with their own groups of interns.
The residents and interns treat the victims of a massive explosion at an apartment building. Alex investigates the cause of the accident. Mama Burke returns to collect her son's things just as Cristina trades her wedding presents in exchange for surgeries.
The new interns are dazzled by the skill level of fellow intern George, while Lexie helps keep his "repeater" status a secret. Meredith half-heartedly helps Lexie with her first emergency patient. Sloan and Richard attempt a radical new surgery to save a woman's ability to speak. George is compelled to tell Callie of his past indiscretion with Izzie. Really Old Guy awakes from his coma and wants to die.
The Chief's wife, Adele, rushes their niece to Seattle Grace, the hospital where she once had her prom. Izzie reveals her feelings for George to a mutual friend, and the reaction is not what she expects. Derek teaches Cristina how to be a better teaching resident. The world's oldest living intern, Norman, misdiagnoses one of Meredith's patients.
It's Halloween, and the day is full of surprises for the doctors of Seattle Grace. Alex receives an unexpected and welcome visit from his former patient, Ava/Rebecca.
With his marriage in turmoil, the Chief turns to his fellow male surgeons for a "gentleman's evening." Cristina and Izzie heatedly compete for the same cardio surgeries and the favor of Dr.
George and Izzie worry that they don't have any romantic chemistry. Derek asks for more than a physical connection from Meredith. Much to his own surprise, Mark develops a crush on a Erica Hahn.
A school bus crash floods Seattle Grace with teenagers, reminding everyone of their high school days. Miranda struggles with her self worth when a friend from high school comes to the hospital. Derek goes out on a date with Sydney Herron. Meredith sees her father for the first time since her stepmother's death when he shows up drunk at the hospital. Rumors fly about Izzie and George's relationship.
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 because of her race. Ava returns for Alex and meets his other girlfriend in the process.
Meredith furiously works to save the life of a paramedic trapped inside an ambulance, as her sister, Lexie, holds the life of a patient in her hands. Derek must rely on the help of a nurse to save a patient's life, as Bailey struggles to balance her personal life with her work.
Bailey's family faces a medical trauma just as her marriage is falling apart. A surprise visit from George's mother comes as a shock to both Izzie and Callie. A faith healer challenges Erica and Alex's beliefs in traditional medicine. Derek must deal with the aftermath of his kiss with Rose.
It is six weeks after Derek and Meredith ended their relationship and Derek began dating Rose. Meredith, Alex, Izzie and Cristina, compete in a surgical contest, with Bailey serving as judge. Interns George and Lexie adjust to their new, squalid apartment. Callie finds a friend in her roommate, Cristina's nemesis, Erica Hahn.
Addison returns to Seattle Grace to perform an operation and is taken aback by all of the changes in her old co-workers' lives. Meredith and Derek's clinical trial has its first patient. Rebecca/Ava returns with shocking news for Alex - she's pregnant. Callie worries that Erica might be a lesbian and might be interested in her.
The nurses' objections to McSteamy's trysts lead to the instating of a new "date and tell" policy. News of Burke's latest career achievements force Cristina to face her feelings for her ex. Meredith and Derek admit a veteran soldier into their clinical trial. Callie turns to Sloan in her time of need.
Dr. Wyatt refuses to let Meredith give up on therapy. Alex learns the truth about Rebecca's pregnancy. The Chief insists that Erica perform a risky surgery on his mentor. After receiving news about Burke, Cristina continues to do things contrary to her nature, going so far as cleaning her always-messy apartment.
Meredith and Derek have one last shot at a successful outcome in their clinical trial, as the other surgeons work together to free a boy from a hardening block of cement.
Izzie helps Alex care for an ailing Rebecca. Lexie discovers critical information about George's intern status - that he only failed the intern exam by one point. Callie realizes she has feelings for Hahn.