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.

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.

A face familiar to one of the year-twos shows up and dredges up issues that were never really dealt with. A teen soccer player needs counseling because of his father and surgery for an injury he sustained while playing the game. Another patient's, named Courtney, finds out that her cancer is back.

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.

Addison visits Seattle Grace because they need skills that only she has. Rebecca/Ava returns with news for Alex. Meredith and Derek's clinical trial experiences one or two developments.

A couple undergoes surgery. Derek and Meredith's clinical trial gets a second shot from a new patient. Izzie helps Alex. McSteamy hooks up with someone.

As Meredith and Derek begin to find that their "happily ever after" is anything but easy, Cristina develops a crush on a military doctor who brings in a trauma patient. Meanwhile, the Chief and his staff cope with the news that Seattle Grace is no longer considered a top-tier teaching hospital.

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.