A fourth-generation Coloradoan, DeGette was born in Tachikawa, Japan while her father served in the armed forces. She graduated with honors from Colorado College in 1979 and earned a Juris Doctor degree from New York University in 1982. She then returned to Denver and began a successful law practice focusing on civil rights and employment litigation.

Long active in Denver politics, she was elected to the Colorado House of Representatives in 1992. She was reelected in 1994 and chosen as minority whip. She authored a law that guarantees Colorado women unobstructed access to abortion clinics and other medical care facilities, popularly known as the "Bubble Bill." She also authored the state Voluntary Cleanup and Redevelopment Act, a model for similar cleanup programs.

1st District Congresswoman Pat Schroeder didn't run for a 13th term in 1996, and endorsed DeGette in the Democratic primary. She won the primary with 55 percent of the vote, which all but assured her of election in the heavily Democratic district (the 1st has been in Democratic hands for all but two years since 1933). She won in November with 57 percent and has been reelected four times against token Republican opposition. She won a fifth term in 2004 with a district-record 76 percent.

In Congress, she serves on the Energy and Commerce Committee, where she is the only Coloradoan; she also serves as the co-chair of the Congressional Diabetes Caucus and the Pro-Choice caucus. She has risen through the ranks of the Democratic leadership and now serves as a chief deputy whip.