Here are five things to watch for on Thursday night:
1. Will Biden go where Obama didn't?
Biden is not shy on the campaign trail; the day after last week's first presidential debate, the vice president attacked Republican nominee Mitt Romney in a way that many Democrats had wished President Barack Obama would have done the night before.
How aggressive will Biden be in going after the man at the top of the GOP ticket rather than the man he'll share the debate stage with? Will Biden highlight the "47%" controversy, Bain Capital and Romney's tax returns?
"The vice president likes laying out the contrast between the Romney-Ryan extreme agenda and the plans he and the president have to move this country forward and we fully expect that to continue Thursday night," an Obama campaign official told CNN.
With the polls tightening both nationally and in key battleground states after last week's debate, the stakes for the showdown between the running mates have increased.
"Biden needs to play offense, not defense," said Democratic strategist and CNN contributor Paul Begala, who is a senior adviser for a pro-Obama super PAC. "Attack the Romney-Ryan plan to cut taxes for the rich and raise them on the middle class. Dissect the Romney-Ryan plan to end Medicare as we know it. Point out that if Romney had been president, Osama bin Laden would be alive and GM would be dead. And be prepared to body-slam Ryan when -- not if -- he fibs."
2. The wonk trap
Paul Ryan likes to call himself "a numbers guy."
Indeed, wonky budget talk is Ryan's calling card. It's the primary reason he has captured the hearts of conservative elites in Washington, who see him as the second coming of Jack Kemp.
But fiscal wonkery was quicksand for Obama during last week's debate. His dreary reliance on budget math over pointed political arguments contrasted sharply with Mitt Romney, who presented his ideas with vigor and clarity, despite obvious questions about the factual underpinnings of his ideas.
Can Ryan avoid getting bogged down in the arithmetic that so thrills him? An adviser to the GOP vice presidential nominee told The National Review's Robert Costa this week that Ryan "may be over-preparing" for his showdown with Biden.
By some accounts, Ryan has bristled at platitude-driven demands of the campaign trail. He'd rather be talking substance, on the road with a PowerPoint presentation about Medicare costs.
The challenge for Ryan on Thursday, though, is to present the Romney vision to millions of voters without sounding too much like the Beltway think tank staffer he once was.
He's done a solid job of that since Romney put him on the GOP ticket in August. Now, on the biggest stage of his career, he has to abandon some of the Capitol Hill tendencies that made him a star in the first place.
3. Will Biden put Social Security in play?
In the House, Paul Ryan has backed moving Social Security funds to private investment accounts as a way to make the popular entitlement program more solvent.
Ryan's past proposals would seem to tee up what's usually a winning political argument for Democrats: that the Republican ticket wants to gut Social Security to help their old pals on Wall Street.
But to the bewilderment of Democratic strategists, Obama appeared to take the issue off the table in the first debate.
"I suspect that on Social Security, we've got a somewhat similar position," Obama said. "Social Security is structurally sound. It's going to have to be tweaked the way it was by Ronald Reagan and Democratic Speaker Tip O'Neill. But it is, the basic structure is sound."
The Obama campaign scrambled to clarify last week that yes, in fact, the two candidates have fundamentally different views on Social Security.
"The choice is clear: President Obama will never privatize Social Security or undermine retirement security for middle-class Americans," read a post on the Obama campaign website that went up after the debate. "The same cannot be said for Romney."
Will Biden try to score fresh points by raising the issue of Social Security privatization against Ryan? Or did the president already holster one of his party's most effective political attacks?
4. The age gap
"I am not going to exploit for political purposes my opponent's youth and in experience."
So went Ronald Reagan's famous line in one of his 1984 debates against Democratic challenger Walter Mondale.
Will Biden have a similar quip ready on Thursday?
OK, Biden is not nearly as old as Reagan, who was 73 at the time of his re-election. But at 69, he has almost three decades on Ryan, his 42-year-old debate opponent.
Biden is also known for his exuberance and devilish charm, so perhaps the age gap won't be as apparent as it was in 2008, when 47-year-old Barack Obama shared a stage with 72-year-old John McCain. Or as it was in 1988, when 67-year-old Lloyd Bentsen debated his boyish vice presidential foe Dan Quayle.
Stylistically, their birthdays might not matter much. But the age difference neatly crystallizes
the arguments being presented by both campaigns.
Will voters choose experience and decide to move forward on the path we're on? Or will they look to a pair of fresh-faced outsiders who offer a new direction?
5. Can Ryan be seen as commander in chief?
Just as Mitt Romney needed to prove last week that he's acceptable to Americans to serve as president, Ryan needs to convey that he's ready to fill in as president in case something happens to Romney. It's one of the top tasks for the challenger's running mate in a vice presidential debate.
We'll be keeping a close watch on Ryan to see if he touts his ability to step in, if needed, to the leading role.
The Romney campaign is confident that the congressman from Wisconsin will pass the test, thanks to Ryan's position as House budget chairman and his mastery of complex fiscal issues.
"It will come down to his competency on the issues, his command of the issues," a Romney campaign official told CNN.
But Republican strategist and CNN contributor Alex Castellanos thinks that this time around, passing the competency test is not as important.
"There is very little pressure for either of these vice presidential candidates to prove they are ready to step into the office of president. Both their bosses are relatively young and in great health," Castellanos said.