After months of vitriol, name-calling and even criminal accusations, it's expected up to 100 million viewers will tune in to watch Ms Clinton and Mr Trump duke it out in front of the cameras.
So what should you be looking out for? What will be the hard questions and key issues?
Republican nominee and billionaire businessman Mr Trump has been much maligned for his supposed ignorance on events outside the US border. He has touted his support of Israel and taken aim at Islamic State (IS), but revealed little in how he will deal with a fractious world full of wary allies and apparent hateful enemies of the United States.
Democratic nominee Ms Clinton has a long history in dealing with foreign countries, and her four years as US Secretary of State should serve her well in trying to dominate Mr Trump on foreign policy matters. But Mr Trump will surely attack Ms Clinton and the Democrats over the Obama administration's failure to stop the ongoing conflict and humanitarian crisis in Syria.
How Trump would solve it, though, is anyone's guess.
Mr Trump's distrustful view of immigrants, whether they be illegal or otherwise, have been widely reported. His rather grandiose plan to build a wall along the US-Mexican border was one of his key promises during his campaign, and is sure to get some air time in tomorrow's debate.
Mr Trump is also incredibly wary of Muslim immigrants, and has proposed banning them entirely from entering the US.
Ms Clinton is a long-time supporter and champion of immigrant's rights going back to her student days, and has looked to curry favour and votes from the millions of ex-pat Mexicans living in the US throughout her campaign.
Expect this topic to get nasty. Mr Trump will play his usual hard-line act, while Ms Clinton will look to counter with empathy and understanding. Mr Trump knows full well immigrants helped build the US, but he's constantly looked to turn immigrants into the bad guys to win votes from uneducated, largely white swing voters.
Millions of Americans struggle to afford health insurance, and have far worse access to care than people living in countries with effective publicly funded healthcare systems, such as the UK, France or New Zealand.
Ms Clinton wants to expand Barack Obama's controversial health programme, "Obamacare", which Republicans have often labelled an exercise in socialism or communism.
Mr Trump wants to completely kill Obamcare and will no doubt give his dubious reasons for doing so during the debate. He views socialised healthcare as un-American and against the nation's capitalist principles.
The US has the world's largest military force, and whoever wields that power holds a very powerful sword.
Ms Clinton has proposed a more cautious approach than Mr Trump, wary of a new Cold War-style build-up of US military might that might lead to another potential flashpoint in the Middle East.
Mr Trump supports military expansion. He wants boots on the ground hunting IS and terrorists, and views a powerful military force has a sense of US national pride.
America's deeply religious and conservative voting block is a mighty beast. While abortion and gay marriage are both legal, many conservative states would like to see that changed.
Ms Clinton is pro-abortion and gay marriage, while Mr Trump is not.
Expect these issues to prove divisive and inflammatory.