Littleford guest-starred on numerous television programs during the late 1990s and 2000s such as Spin City (where she had a multi-year occasional role), The West Wing, Family Guy, and Frasier. Littleford was also a celebrity commentator on VH1's I Love the 80s Strikes Back in 2003, I Love the 90s in 2004, I Love the 90s: Part Deux in 2005, I Love the New Millennium and The Great Debate in 2009. She was the female lead on the short-lived Fox series Method and Red, and also starred as Ben Tennyson's mother Sandra in Ben 10: Race Against Time, and reprised the role in the Ben 10: Alien Force episode 20 and again in Ben 10: Ultimate Alien. More recently, Littleford appeared in TV commercials for Laughing Cow cheese and a hotel chain.
She starred in the Disney XD original show I'm in the Band, the 2010 Disney channel movie Starstruck, and played Suzanne Berger on MTV's The Hard Times of RJ Berger and Dana on ABC's Desperate Housewives. She also plays the Cascade Kitchen Counselor on the TV commercials (2012). She currently has a starring role in the Disney Channel original series Dog with a Blog.
Littleford was born in Florida, the daughter of Jackie, a professor, and Philip O. Littleford, a cardiologist and inventor. She lives in Los Angeles, California with her husband, producer and director Rob Fox. Littleford and Fox have one son, Jackson Oliver Fox, born on July 30, 2005. The couple adopted a daughter, Halcyon ‘Hallie’ Juna, who was born on March 23, 2012.