In his year and a half long bid for the White House, one of the former Massachusetts governor's main arguments is that thanks to his business background, he can do a better job creating jobs than Obama has done over the past four years. The debate in Denver gives Romney a well-watched platform to make his case.
Romney "has to explain a rationale that he's offering change that would make things better over the next four years," says Castellanos. "This is his opportunity to present his counternarrative, that Obama's growing the wrong economy. He need say that Washington's economy is doing just fine, and ask how your economy's doing."
Whichever candidate better presents and sells his economic narrative will go a long way toward determining who wins the debate, and more importantly, who wins the minds of undecided voters.
4. Can Obama get women and Latinos into the discussion?
Romney carved out positions during the Republican primaries that have landed him in a deep hole with Hispanic and female voters.
Remember the so-called "war on women"? In the course of trying to out-conservative his GOP rivals, Romney vowed to end federal funding for Planned Parenthood, came out against a law that mandates insurance companies cover contraception services and did not take a stand on the Lilly Ledbetter Fair Pay Act that Obama signed in 2009. He has also said he wants the Supreme Court to overturn Roe v. Wade.
Romney also rankled Hispanics by calling elements of Arizona's tough immigration law a "model" for the nation, floating the notion of "self-deportation" and promising to veto the DREAM Act, which would offer a path to citizenship for young illegal immigrants.
The Obama campaign has exploited these positions to great effect, pushing them to women and Hispanics in swing state campaign appearances, targeted e-mails and niche media efforts. (Don't know who Cristina Saralegui is? Google her.)
Republicans have criticized those tactics as a cynical distraction from the sagging economy, but they're working.
A Quinnipiac poll of Ohio likely voters released last week, for instance, showed Romney losing women to Obama by a staggering 25-point margin.
Internal Romney polling, meanwhile, has him badly trailing Obama among Hispanics -- and it's been that way all year.
With more than 50 million people expected to tune in Wednesday evening, don't expect the president to pass up a golden opportunity to keep female and Hispanic-oriented issues in the national spotlight.
5. Taking the zing out of zingers
It was just one line in a New York Times story last weekend about each candidate's debate cram sessions, but it grabbed a lot of attention.
"Mr. Romney's team has concluded that debates are about creating moments and has equipped him with a series of zingers that he has memorized and has been practicing on aides since August," reporters Ashley Parker and Peter Baker wrote in the paper.
Romney advisers are correct that voters are likely to walk away from the debate talking about distinctive moments -- audible sighs, body language, repeated use of phrases such as "lock box" -- rather than factoids about Medicare Advantage or sequestration.
The Obama team predictably pounced on that one.
"We also saw in reports that Mitt Romney and his team have been working on zingers and special lines for months," Obama spokeswoman Jennifer Psaki told reporters over the weekend. "That's not what the president's focus is on. So if you're expecting that, that's probably not what he's going to deliver on."
Romney delivered his lines with precision during the Republican primary debates and probably will again on Wednesday.
But if it comes to pass that Romney jabs at Obama with a sharp attack or humorous quip, you can be sure the president's allies will be ready to mock Romney's reliance on prepared "zingers" to diminish his stature and performance.