While Obama holds a lead in several key battleground states, the race nationally has been locked in a dead heat for months. The debate offers an opportunity for Obama or Romney to gain some momentum and break the logjam.
Here are five things to watch for on Wednesday:
1. Who's presidential?
The first and most important test for the president and Romney in this opening debate is to act like they belong in the job.
We've heard a lot of bickering on the campaign trail, and there's plenty of talk that zingers could decide who wins or loses the showdown in Denver. But to most Americans, this debate is really about which candidate has the composure and stature to serve in the Oval Office.
"If either the president or Romney can't pass this test, the rest really don't matter. Big ideas from a small person won't make you president of the United States," says Republican strategist and CNN contributor Alex Castellanos. "When the moment comes, this is like proposing to your wife. This is a big moment."
Thanks to already serving nearly four years in the White House, Obama starts with the advantage, but he can't afford to play it safe at the debate.
"Playing it safe allows Romney to dominate the agenda and put Obama on defense. Either you're on offense or defense, and defense loses," adds Castellanos, who was a senior adviser to Romney in 2008 election.
By comparison, Romney has to do double duty: Stay on offense but also look presidential.
What does Obama have to do?
"Keep cool -- which comes naturally to him," says Democratic strategist and CNN contributor Paul Begala. "Make it about the middle class, not himself or Romney."
2. Can Romney get Libya into the discussion?
The first debate is officially devoted to domestic policy.
Matters of national security and foreign policy are being left to later debates, but Romney may not be content to wait that long with the drip-drip-drip of conflicting news continuing to emerge from Libya, where four Americans -- including U.S. Ambassador Chris Stevens -- were killed in an apparent terrorist attack last month.
Serious questions have been raised for the Obama administration in the wake of the Libya attack: Was the American compound in Benghazi secure before the attack? Did U.S. officials fail to heed warnings or concerns about possible violence? Why has the president been so hesitant to describe the incident as a "terrorist attack"? Why is the scene still not secure, more than two weeks after the attack?
"We've seen a confused, slow, inconsistent response to what is now very clearly known as a terrorist act," Republican vice presidential candidate Paul Ryan said on Monday. "It's really indicative of a broader failure of this administration's foreign policy and the crisis that is taking place across the Middle East."
Polls indicate that the economy remains the top issue for voters, and Romney advisers in Boston believe the same. And when it comes to foreign policy, more voters trust Obama than Romney, polls show.
But there are hints of vulnerability for the president on Libya crisis. In a recent Fox News poll, 43% of voters said they disapproved of Obama's performance on Libya, while 39% approved.