"Secret is usually ugly. It's kind of sleazy, slimy, secret money," said McCaskill.
The Missouri senator, one of the most vulnerable Democrats up for reelection in 2012, has faced a barrage of negative advertising from special interest groups, as conservatives work to oust her from the Senate.
For her part, McCaskill is aiming to appeal to Missouri voters by undercutting the credibility of groups like American Crossroads.
When pressed on whether the people behind the attack ads would face attacks themselves if revealed to the public, McCaskill responded sarcastically, "wouldn't that be unfair?"
Colbert pushed back saying that she was a public official and the ads were paid for by private citizens.
"I certainly expect attack ads in commercials, but what I don't expect is for this all to be secret," McCaskill said.
McCaskill told Colbert that she is calling on millions of supporters to donate five dollars to her campaign to combat what she said has been $4.3 million in anonymous money spent to boot her from the Senate.
"That's how we're going to clean this up, is put a lot of little money in, then we can take the large money out," she added.
The senator's campaign is spending about $300,000 on a statewide 30-second spot touting her commitment to fighting the special interest groups.
"They just keep coming back. Secret money, attacking Claire McCaskill," says the narrator. "These big oil and insurance companies don't want you to know who they are."