Addison is a highly regarded neo-natal surgeon and a fellow of the American College of Surgeons, Addison is also a board certified OB-GYN with fellowships in maternal-fetal medicine and medical genetics. She also completed two years of study on cystic fibrosis. In addition, she is also one of only a handful of surgeons in the world who know how to separate fetal blood vessels.

She was married to Derek Shepherd for eleven years before having an affair with his best friend, plastic surgeon Dr. Mark Sloan, which prompted Derek to leave New York for Seattle. There, he met Dr. Meredith Grey with whom he started a relationship. Addison then arrived in Seattle at Richard's behest, and confronted Derek on his affair by introducing herself to Meredith as his wife. This left Meredith feeling distraught and betrayed, and she ended things with Derek.

A possibility of a relationship between her and Alex Karev has been hinted at, when she kissed him in Joe's bar. Even after he rejected her affections, she continued to lust after him from afar. She has (along with Mark) decided to abstain from sex for 60 days. If Dr. Sloan completes the challenge, she is willing to try a real relationship with him; however, it is she who fails. She engages in a sexual encounter with Alex at the hospital and Mark learns of this after witnessing them stumbling out of an on-call room. She is spared from confessing, however, when Mark lies to her by telling her he had broken their promise long before. According to many of the show's allusions, Addison then decides to pursue Alex Karev. Her advances are once again rejected, however, hinting at the potential departure of Addison though she has expressed immense interest in being the next Chief of Surgery.

In the pilot episode, it was revealed that Addison can no longer conceive, as her antral follicle count was only two. She rekindles with her old Medical School friends Dr. Sam (Jackson) Bennett, and his former wife Dr. Naomi Bennett.

Addison is considered one of the best surgeons in her field in the world (patients often travel across the country to receive medical and surgical care from her), but with her relocation to Los Angeles her exact Medical Service is in doubt.