The season followed the continuation of the surgical residency of five young interns, as they experience the demands of the competitive field of medicine, which becomes defining in their personal evolution. Although set in fictional Seattle Grace Hospital, located in Seattle, Washington, filming primarily occurred in Los Angeles, California. Whereas the first season mainly focused on the impact the surgical field has on the main characters, and the second one provided a detailed perspective on the physicians' private lives, the third season deals with the tough challenges brought by the last phase of the surgeons' internship, combining the professional motif emphasized in the first season, with the complex personal background used in the second. Through the season, several new storylines are introduced, including the arrival of Dane's character, Dr. Mark Sloan, conceived and introduced as an antagonizing presence.

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