Meredith Grey, the daughter of the once-renowned surgeon Ellis Grey, becomes an intern at the Seattle Grace Hospital. She meets fellow interns Cristina Yang, Isobel "Izzie" Stevens, George O'Malley and Alex Karev who become her closest friends during the intern program. She finds herself working with renowned surgeons such as the heart surgeon Preston Burke and Richard Webber, chief of surgery and old friend of her mother. She finds herself working under her one night stand and famous neurosurgeon Derek Shepherd and working with her resident Dr. Miranda Bailey also known as The Nazi.

The season continued to focus on the surgical residency of five young interns as they try to balance to the challenges of their competitive careers, with the difficulties that determine their personal lives. It was set in the fictional Seattle Grace Hospital, located in the city of Seattle, Washington. Whereas the first season put the emphasis mainly on the unexpected impact the surgical field has on the main characters, the second one provides a detailed perspective on the personal background of each character, focusing on the consequences that their decisions have on their careers. Throughout the season, new story lines were introduced, including the love triangle between Meredith Grey, Derek Shepherd, and Addison Montgomery, the main arc of the season. Also heavily developed was the story line involving Izzie Stevens' relationship with patient Denny Duquette, which resulted in critical acclaim and positive fan response.