Some potential scenarios for the event at the University of Mississippi in Oxford:
The topic for the first debate is national security and foreign policy, a strength for McCain, a 26-year veteran of Congress who has become one of Washington's leading voices on military policy. Obama aides, looking to set expectations, say that should give McCain an edge in the first encounter.
The Wall Street turmoil has dominated the campaign for nearly two weeks, and is expected to be raised in the questioning even though domestic issues are not on the agenda. Polls show voters favor Obama on economic issues, and the topic has helped him pull slightly ahead of McCain in some recent polls.
McCain, 72, and Obama, 47, will present a stark generational contrast when they stand side by side on the debate stage. Whether it looks more like the past versus the future or the old pro versus the callow rookie could play a role in setting voter impressions of the candidates.
Neither has been a particularly distinguished debater. McCain has a blunt and straightforward style; Obama can be much more cool and diffident. McCain's reputation for being easily angered can work against him, while Obama will have to fight a tendency to sound too nuanced and professorial.
The audience for the nationally televised encounter is expected to dwarf the 40 million who watched the acceptance speeches by McCain and Obama at their nominating conventions, and could surpass the 62 million who watched the first 2004 debate between Democratic Sen. John Kerry and Republican President George W. Bush.