Willes played the recurring role of Agent Karen E. Kosseff, a government counselor, on the TV show The X-Files. She also appears in a minor recurring role on the show Reaper on The CW, as Gladys, a demon from Hell who works in the DMV. She was nominated for a Leo Award in 2008 for that role. Like her Dead Like Me co-star Callum Blue, she was cast as the villain Granny Goodness on The CW's Smallville's tenth and final season (Blue appeared in the previous season as Zod). She also had a small role in the award-winning film Trick r Treat starring Anna Paquin, which also featured another Dead Like Me co-star, Britt McKillip. She also played Vera Kane on CW series the 100.