Besides starring in Bride of Chucky, Tilly can be seen starring in the soon-to-be released independent film, Relax, It's Just Sex. She also lends her talent to Columbia's upcoming Stuart Little, a family comedy based on the book by E.B. White, where Tilly gives voice to the character of Stuart's biological mother (who just happens to be a mouse). Other upcoming films include Bruno, directed by Shirley MacLaine and co-starring MacLaine, Kathy Bates and Gary Sinise, and October Films' The Muse, starring Albert Brooks. Tilly's other feature film credits include Bound, The Getaway, Made in America, The Fabulous Baker Boys, Let It Ride and Shadow of the Wolf.

On television, she starred in the Fox series Key West with Fisher Stevens, and the ABC series Shaping Up with Leslie Nielson. She starred in Showtime’s Heads with Jon Cryer, for which she received a Gemini Award nomination for Best Actress. Tilly also had recurring roles on Hill Street Blues and The Garry Shandling Show, the latter of which garnered her a Cable ACE nomination for her role as Shandling’s girlfriend, Angelica. Her other television appearances include Moonlighting, Cheers, Dream On, Edie and Penn and The Gun, directed by Robert Altman.

Tilly won a Theater World Award for her work in Tina Howe’s play, One Shoe Off at the Joseph Papp Theater. Her other stage work includes Boy’s Life and Tartuffe at the Los Angeles Theater Center, Baby With The Bathwater and The Wool Gatherer at the Los Angeles Public Theater, and Vanities, for which she received a Dramalogue Award.