He was first elected to the United States House of Representatives in 1992 and served four terms there, from 1993 to 2001, being reelected in 1994, 1996 and 1998. He declined to run for re-election in 2000 in order to run for Governor, but he was narrowly defeated by his Democratic opponent, Bob Holden 50%-49%.
In that same election, Governor Mel Carnahan, who remained on the ballot for election to a senate seat even though he had died in a plane crash a month before the election, defeated John Ashcroft. Carnahan's death was an event that would have great effect on Talent's political future, first of all because it probably contributed to his loss to Holden. It would allow him to be elected Senator, however. Though by prior arrangement Mel's widow, Jeanne Carnahan was appointed Senator in her husband's place, a special election was required. It was held during the midterm election of November 2002. Talent received the Republican nomination and defeated Jeanne Carnahan. He was sworn in later that month.