She earned an Academy Award nomination for her stunning performance in Transamerica, as well as a Golden Globe Award and Independent Spirit Award for the same role. She has also been honored with an Emmy and a Screen Actors Guild Award for Best Lead Actress in a Comedy Series for her role on Desperate Housewives.
On the small screen Huffman was seen in 2004 in the television movie Reversible Errors, with William H. Macy, Tom Selleck and Monica Potter.
Huffman is a founding member of the Atlantic Theater Company, an off-Broadway theater company where she has been featured in numerous plays, including Dangerous Corner, Shaker Heights and The Joy of Definitely Going Somewhere.
Huffman resides in Los Angeles with her husband, actor/director William H. Macy.