The season follows the story of surgical interns, residents and their competent mentors, as they experience the difficulties of the competitive careers they have chosen. It is set in the surgical wing of the fictional Seattle Grace Hospital, located in Seattle, Washington. A major storyline of the season is the characters adapting to change, as their beloved co-worker Stevens departed following the breakdown of her marriage, O'Malley died in the season premiere—following his being dragged by a bus, and new cardiothoracic surgeon Teddy Altman is given employment at the hospital. Further storylines include Shepherd being promoted to chief of surgery, Seattle Grace Hospital merging with the neighboring Mercy West —introducing several new doctors, and several physicians lives being placed into danger—when a grieving deceased patient's husband embarks on a shooting spree at the hospital, seeking revenge for his wife's death.

• Ellen Pompeo
• Chandra Wilson
• James Pickens Jr.
• Kevin McKidd
• Caterina Scorsone
• Camilla Luddington
• Kim Raver
• Jason George