After serving for eight years in the U.S. House of Representatives and then working as a lobbyist, he ran for Governor of Missouri in 2000, losing to Democrat Bob Holden.

[6] Following Donald Trump's victory in the 2016 presidential election, Talent was rumored to be on the short list for United States Secretary of Defense,[7] a position ultimately offered to James Mattis.

[8] His father, Milton Oscar Talent, was the son of Russian Jewish immigrants, and was the first in his family to go to college, graduating from Harvard Law School.

[9][10] Talent's mother, Marie Frieda (née Matthes), was an independent court reporter who was raised on a small farm near DeSoto, Missouri.

In the 1992 House of Representatives election, Talent defeated Bert Walker, the cousin of then-president George H. W. Bush and won the Republican nomination for the state's 2nd Congressional District, based in St. Louis's western suburbs.

Carnahan received more votes than his Republican opponent, incumbent senator (and later United States Attorney General) John Ashcroft.

Lieutenant Governor Roger Wilson, as he had promised before the election, appointed Carnahan's widow, Jean, in her husband's place.

[25] Talent was criticized for not returning the money received from Americans for a Republican Majority (ARMPAC), a PAC formed by Tom DeLay.

Having lost his reelection bid, Talent was considered a possible candidate for Governor of Missouri in 2008 after incumbent and fellow Republican Matt Blunt decided to not seek re-election.

[40] In 2005, Talent was tied for the third-highest rating among all senators and representatives as determined by the Republican Liberty Caucus, which promotes "liberty-minded, limited-government individuals to office.

[43] In addition to renewable fuels, Talent supported drilling in the Arctic as a step in the direction of energy independence, which he sees as critical to national security.

[45] Talent called for waiving a one percent penalty for senior citizens who missed the deadline to sign up for the program.

[49] Talent sponsored legislation to cap the annual percentage interest rate for payday loans to military service personnel from an average of around 39% to 36%.

This move followed criticism by Talent's opponent in the 2006 election, Claire McCaskill, as well as pressure from Missouri business interests that oppose restrictions on stem cell research.

Though this reversal was criticized as being politically motivated,[53] Talent told the Associated Press, "The technology is changing all the time and so I'm always considering whether there is a better way to strike the balance.

"[54] Talent suggested that moral concerns might be put to rest through a possible future scientific breakthrough – replicating embryonic stem cells without the use of cloned embryos.

There was a ballot-initiative in Missouri in November 2006 to amend the state constitution and allow, in line with federal law, stem cell research and treatment.

He is Vice Chair of the bipartisan Commission on the Prevention of WMD proliferation and terrorism, which has concluded that, unless action is taken, a biological attack within the United States is increasingly likely and will become a probability by 2013.

[63] Together with former Senator Bob Graham, Chairman of the commission, he has criticized the federal government's readiness to deal with major public health crisis'.

On January 4, 2010, the two senators published an op-ed in the Washington Post, arguing that an unsatisfactory response to the 2009 flu pandemic shows the need for better medical emergency plans.