Talent ran for re-election for his first full term; his Democratic opponent was Missouri State Auditor Claire McCaskill.

In 2000, the late Missouri Governor Mel Carnahan, a Democrat, narrowly defeated incumbent Republican Senator John Ashcroft 50% to 48%.

It had voted for the winner of every presidential election starting in 1904, except for in 1956, when the state narrowly favored Adlai Stevenson over Dwight D. Eisenhower.

Senator Kit Bond was re-elected by a decisive margin, and Matt Blunt won the election for Governor, narrowly defeating state auditor Claire McCaskill.

Talent, anticipating a tough re-election battle and attempting to dissuade challengers, had accumulated a large campaign fund.

Talent started statewide advertising on August 1, 2006, forcing some observers to suggest that Talent was on the ropes and therefore needed to reassert his image (damaged recently by his "flip-flopping" on stem cell research, his opposition to raising the minimum wage and a general feeling of antipathy from the body politic regarding his lack of notable achievements while in the Senate)[2] and pull ahead in a statistical dead heat.

On February 10, 2006, Talent withdrew his support for the bill,[4] citing the need to balance research and protection against human cloning.

This move followed criticism by Talent's Democratic 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 widely criticized as being due to politics,[5] 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.".

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

Fox, who has Parkinson's disease, appeared in a television campaign commercial for Claire McCaskill in late October, stated that Talent wanted to criminalize embryonic stem cell research.

The commercial, which was one of many Fox had appeared in for politicians of both major political parties supportive of such research,[10] made national headlines.

[11] Rush Limbaugh, conservative radio talk show host, commented on the TV commercial, saying that Fox was "really shameless" and that he was "either off his medication or acting.