Donald Trump and Joe Biden will meet on the debate stage at the Case Western Reserve University and the Cleveland Clinic in Ohio.
The 90-minute prime-time event is an opportunity for millions of Americans to compare the policies and personalities of the two presidential contenders who are side-by-side.
Trump has been trailing the Democrat former vice president in national polls for months but the race is showing signs of tightening in some decisive swing states.
Debate moderator Chris Wallace, a Fox News Channel host, has selected the topics. He will challenge the pair on their records, the COVID-19 pandemic, the economy, race and violence in American cities, the future of the Supreme Court and the integrity of the election.
But other subjects making the headlines – such as revelations about Trump’s tax affairs – could make an appearance.
Presidential debates have long been viewed as pivotal moments in the race for the White House. With the pandemic scuppering most traditional campaigning, this one could be especially significant.
Biden’s preparation has focused on hammering home his message that Trump has failed the American people on the economy and the pandemic. Advisers say he needs to avoid rising to Trump’s insults.
He also needs to put to bed Trump’s slurs that “Sleepy Joe” lacks the energy and mental focus to take on the presidency.
At 77, he would be the oldest person ever inaugurated as president, a record currently held by Trump.
In Democratic primary debates, Biden at times appeared flustered and halting, notably when he was attacked by his now running mate Kamala Harris.
Trump is said to have dispensed with formal debate preparation. His campaign believes he subjects himself to enough hostile questioning every day to be sufficient.
He demonstrated in his debates with Hillary Clinton in 2016 that, like most things, he views them as reality television. His belligerent, combative and overbearing style was unlike anything American politics had ever seen.
Perhaps the busiest people on the night will be the army of fact checkers tuning in. Biden has repeatedly labelled Trump a liar.
There is an urgency for both campaigns in this first debate with millions of Americans voting early. Trump’s repeated questioning of the legitimacy of the election, and postal voting in particular, is almost certain to feature.
The question is whether the debate will dramatically alter the course of the race. In recent election years, the winner on the stage isn’t always the winner on election night.
And, with five weeks to go, in an America as angry and divided as rarely before, how many of them have not already made up their minds?
Watch and follow the first 2020 US presidential debate live on Sky News and Sky News online and mobile from 2am on Wednesday.