Talent's position on the war in Iraq and Afghanistan was to stay the course and complete the mission.
He said it was necessary to oust Iraqi leader Saddam Hussein and had he been in the Senate in 2002, he would have voted to go into Iraq even if the country did not possess weapons of mass destruction.
McCaskill criticized Talent for defending what she described as President Bush's stubborn foreign policy.
She also referenced the National Security Agency's wiretapping program, which has been challenged in federal court, by saying that although intelligence-gathering is necessary, it should be done within the guidelines of the Constitution.
On the issue of stem cells, Missourians will encounter a referendum on the Nov. 7 ballot that would allow Missouri's stem cell researchers to conduct any research permitted under federal law without any interference from the state legislature.
McCaskill expressed support for the referendum, while Talent did not. He said that cloning the earliest stages of human life "goes too far."
The two candidates also differed on whether the United States should hold direct talks with North Korea about its nuclear program -- something President Bush has resisted. Talent said the Clinton administration tried such talks, to no avail.
McCaskill said she would not be opposed to talks with North Korea and that it is important to negotiate with any country that poses a danger.
The debate in Clayton, Mo., was the third in a series of five before the November elections.
During an appearance on the Oct. 8 NBC program "Meet the Press", the two candidates clashed over the war in Iraq and other matters, with Talent accusing McCaskill of taking a weak stand on Iraq and McCaskill portraying Talent as a politician who has lost touch with the people.
The two still appear to be running neck and neck in polls.