Aside from policy differences, voters will have their first opportunity to see for themselves how Obama and Romney stack up against each other in temperament and values.
"They need to look presidential," said Paul Beck, a presidential scholar at the University of Ohio. "Presidential means there has to be a certain augustness to them. They can't be too negative. They can't look like they're dismissive and arrogant. They have to be articulate, they shouldn't be argumentative."
Tune in to ABCNews.com on Wednesday for livestreaming coverage of the first 2012 Presidential Debate from Denver. Coverage kicks off with ABC News' live preview show at noon, and full debate coverage begins at 8 p.m.
Expect the candidates to eschew the highly effective but negative attacks of the campaign and take the high road.
As recently as Monday, the Obama campaign released an ad attacking Romney for hiring "sweatshop labor" in China.
And Romney comes to the debate after taking heat from Republicans and Democrats for appearing to politicize the death of Ambassador Chris Stevens in Libya.
To be sure, debates aren't the venue for hugs and smiles. But overly aggressive or aloof candidates have resulted in withering reviews afterward.
"There have been debates where style has certainly trumped substance," said Bob Shrum, a veteran Democratic strategist who worked on several campaigns, including former Vice President Al Gore's run against George W. Bush."The first Gore-Bush debate, where Gore won hands down on the substance of the debate, Republicans did a good job of spinning it as sighs, exasperation and fighting with the moderator," said Shrum.
Gore's sighs and eye rolls didn't come across as negative in the debate hall, but they did on television, Shrum said.
When George H.W. Bush routinely glanced at his watch during a 1992 debate with Bill Clinton, the move telegraphed impatience.
Former presidential candidate Howard Dean, who became known for his impassioned "scream" after the Iowa caucus in 2004, said Obama needed to carefully watch his mannerisms while sharing the stage with Romney.
"It's not what they say, it is their mannerisms. It's how they come across," Dean said on ABC's "This Week With George Stephanopoulos" Sunday. "The president has to avoid being irritable. He's got to roll with the punches.
"He's got to relax, he's got to show a little sense of humor, he's got to be likable," Dean said.
Obama comes to Wednesday's debate with the advantage of rosy poll numbers in several swing states and personal favorability ratings that have hovered at more than 50 percent for the entire campaign.
But Obama has often been criticized for appearing too "professorial." His aides, working to prepare him in Nevada for the debate in Denver, acknowledged that they were grooming him to shorten his answers.
And Romney, who has the advantage of getting extensive debate practice during the primaries, may try to get under Obama's skin.
"In terms of style, I think you're going to see Mitt Romney be fairly aggressive," said Republican strategist and pollster Dan Judy.
When Obama last faced a debate opponent as a presidential candidate, he had little in the way of a record that could be attacked.
"Now he's got a record to defend, and his record is not popular. And he has a tendency to get a little defensive, sometimes irritable when he's questioned on his record," Judy said.
As the challenger, Romney must prove that he can go toe-to-oe with Obama on policy without turning primetime television into a "wonkfest," Shrum said.
And to bounce back from his campaign's pitfalls of the past several weeks, Shrum said Romney won't pass up the opportunity to challenge Obama.
"The challenge for Romney is that he's got to get back in the game. He's got to be aggressive, but he's got to do it in a kind of friendly way," Shrum said. "Confrontational with a smile."