The controversy surrounding the Association of Community Organizations for Reform Now, or Acorn, a left-leaning voter registration group under investigation for voter registration fraud in several states, may also be raised in the debate.
McCain's campaign has attempted to tie the Acorn effort to Obama, who once represented Acorn.
"Acorn is tampering with America's most precious right. There has to be a full and complete investigation," McCain said during a campaign stop in Florida.
"Given the extensive relationship between Barack Obama and Acorn, our campaign also feels that Sen. Obama has a responsibility to rein in Acorn's efforts and to work aggressively against wide-scale voter fraud," the McCain campaign said in a statement today.
Obama can take the more cautious approach tonight.
"For Obama, he's in a do-no-harm mode. ... His big challenge is just to avoid mistakes that become the talk of the campaign trail over the next couple of days," said ABC News' Chief Washington Correspondent George Stephanopoulos.
McCain has a much tougher job, he said.
"He does have to draw some blood on Barack Obama, but if he goes too negative he'll reinforce the impressions that have been built up over the last couple of weeks that he's the candidate on the attack," Stephanopoulos said.
Both the ABC News/Washington Post and the New York Times/CBS News polls found that a spate of McCain attacks on Obama actually hurt McCain instead of Obama, because voters objected to his negative tactics.
Even if McCain scores points over Ayers and Acorn, it may not help him enough because "voters are so focused on the economy," Stephanopoulos said.