The two feisty US senators, personal friends who advocate similar left-leaning agendas but employ different styles, will be the top-ranked candidates on stage for the first evening of a two-night debate featuring 20 Democrats.
Frontrunner Joe Biden takes the stage Wednesday night between senators Kamala Harris and Cory Booker, prominent African-Americans who have strongly criticized the former vice president on racial issues.
The stakes are sky high. The debate is likely to winnow the sprawling field, perhaps by as much as half, ahead of the next debate in September as the party seeks its best nominee to challenge President Donald Trump next year.
"I think right now, it will be Sleepy Joe," Trump said Monday, using his custom sobriquet for Biden, when asked by reporters at the White House if he would be watching the debates.
"I feel he will limp across the line... I think he is off of his game by a lot but I think, personally, it is going to be Sleepy Joe."
For underperformers like Senator Kirsten Gillibrand or Obama-era cabinet member Julian Castro, both polling at under two percent, the prime-time debate could be their final chance for a breakout that keeps their struggling campaigns above water.
The Detroit showdown, broadcast by CNN, is expected to bring more heat than last month's opener, in part because of the expected clash between Biden, Harris and Booker.
After his lackluster June performance when he faced withering critique from Harris over his past record, Biden acknowledged he was ill-prepared to counter the brickbats.
But he said last week he's "not going to be as polite this time."
Amid the sustained sniping, Harris -- who enjoyed a major bump in support with a viral moment against Biden but has slipped to fourth in polling -- signaled she will play fair.
"I will express differences and articulate them," she told reporters Monday in Detroit. "There's no reason we can't be polite."
Biden has managed to maintain his pole position, with around 32 percent support according to a poll average compiled by RealClearPolitics.com.
Warren had been steadily gaining, and briefly moved into second spot on Monday following a strong showing in a Quinnipiac Poll, before falling back to third with 14 percent -- a couple of points behind Sanders.
- 'Radical socialism?' -
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With major appeal among the party's liberal wing, Warren and Sanders share similar political platforms: both support universal health care, tuition-free public college, tax hikes on the wealthiest Americans, a $15-per-hour minimum wage and aggressive regulations on Wall Street.
But while Sanders is a self-proclaimed Democratic socialist seeking to whip up a "political revolution," Warren calls herself a capitalist who advocates a series of fixes to the existing structure, including strict regulations on US markets.
A lot will ride on how the two, and their rivals, articulate their vision for America's future.
Critics warn of the risks of driving the party too far leftward ahead of the election.
Trump has already seized on the shift to warn Americans that all 2020 Democrats have embraced "radical socialism."
Sanders appeared unfazed Monday, reiterating his rallying cry to "take power back from the billionaires and put it in the hands of the people, where it belongs."
While Warren and Sanders will be selling their liberal prescriptions, several moderates join them on stage Tuesday, including Pete Buttigieg, the mayor of South Bend, Indiana who stands fifth in polling.
In the previous debate, Buttigieg upbraided his more liberal rivals over the costs of their ambitious plans like Medicare for All, saying they have "a responsibility to explain how you're actually supposed to get from here to there" and pay for the programs.