Raised in Thermopolis, Wyoming, Enzi attended George Washington University and the University of Denver. He expanded his father's shoe store business in Gillette before being elected mayor of Gillette in 1974. In the late 1970s he worked in the United States Department of the Interior. He served as a state legislator in the Wyoming House of Representatives (1987 � 1991) and the Wyoming Senate (1991 � 1996). During the 1980s and 1990s he worked as an accountant and executive director in the energy industry.
Enzi won a tight primary for election to the U.S. Senate in 1996 and was re-elected by comfortable margins in 2002 and 2008. He has been ranked as one of the most conservative members of the Senate. He is the ranking Republican on the Senate Health, Education, Labor, and Pensions Committee, which he chaired from 2005 to 2007. He was a member of the 2009 Gang of Six which attempted to negotiate a health care reform program.