The first day back at Seattle Grace Hospital is a hectic one, with Meredith, Izzie, Cristina and Alex entering their first year as residents, and they are relishing being in charge and having their own minions to mentor.
The interns are welcomed by newly appointed chief resident Callie (Sara Ramirez), wife of George, who was the only previous intern forced to repeat his internship after failing his exams. He befriends Lexie Grey, Meredith's half-sister, another new intern to join the hospital. The new interns and their mentors all have their hands full when a three-car accident sends multiple casualties pouring into Seattle Grace. Some of the doctors need to deal with their new stressed out interns, while Izzie steps in to impress her new interns on a bizarre medical case involving a deer. Having just returned from her honeymoon, with best friend Meredith, Cristina searches for estranged fiancé Burke and is shocked to hear he has handed in his resignation. Richard (James Pickens Jnr) resumes his post as chief of surgery. Derek, aka McDreamy, (Patrick Dempsey) and Meredith reach an impasse in their relationship, again, and Bailey (Chandra Wilson) wrestles with being passed over for a promotion.

The residents and interns treat the victims of a massive explosion at an apartment building, while 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, Lexie tries to have a heart-to-heart with an unwilling Meredith, and while Callie is overwhelmed with her duties as Chief Resident, Bailey searches for an outlet for her pent-up leadership skills.

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; and George is compelled to tell Callie of his past indiscretion with Izzie.