From the mid-1990s (while at Northwestern University) through 2001, Dudek appeared in various theater productions and on Broadway. She made her Broadway debut in Wrong Mountain in 2000, and won the Connecticut Critics Circle Award for outstanding performance in The Glass Menagerie.

After success on Broadway she made the jump to television, with her first starring role coming on the British comedy drama The Book Group. She has since guest starred on many other shows, including Desperate Housewives (as Karl Mayer's girlfriend in Season 1), How I Met Your Mother (as Ted's Krav Maga-trained ex-girlfriend), Friends, Charmed, Bones (as Seeley Booth's lawyer girlfriend), Numb3rs and Six Feet Under. She also played Lucinda Barry in the pilot episode of Psych, and a teacher who has a sexual relationship with one of her students (based on the case of Debra Lafave) on Law & Order: Criminal Intent.

Dudek had a recurring role on House beginning in season 4, as Amber Volakis, one of forty physicians under consideration by Dr. House for permanent positions on his team. Her character continued to the end of season but was killed in the season 4 finale, "Wilson's Heart". Towards the end of season five her character returned as a drug-induced hallucination. Dudek later appeared in Mad Men as next-door neighbor Francine Hanson, and on Big Love as one of antagonist Alby Grant's wives, both recurring roles.

In 2010, Dudek joined the main cast of Covert Affairs, portraying Danielle Brooks, the sister of the central character.

On film, she played the role of cruise line heiress Tiffany Wilson in the 2004 comedy film White Chicks. She also played Anthony Hopkins' daughter in The Human Stain.

Dudek was born and raised in Greater Boston in the suburb Newton, and attended Northwestern University. She is married to artist Matthew Heller, with whom she has a son, Akiva, born on December 14, 2008.