In 2006, she landed the role of Susan Grey on the ABC drama Grey's Anatomy where she played the stepmother of one of the main characters, Dr. Meredith Grey. Her character was killed off in May 2007. In 2006, Winningham voiced the audio version of Stephen King's Lisey's Story. In 2007, she voiced Alice Hoffman's Skylight Confessions. In 2010, Winningham starred in an episode of Cold Case as main character Lilly Rush's stepmother, Celeste Cooper. In 2011 she appeared in the fourth episode of Torchwood: Miracle Day as character Ellis Hartley Monroe. She also starred in miniseries Mildred Pierce and Hatfields & McCoys and garnered another two Emmy nominations. In 2012, she appeared Off-Broadway as Beth, the mother in an intellectual, though dysfunctional, British family, in the award-winning comic-drama Tribes by Nina Raine.