Democrats have strong prospects of winning the White House in November, given the weak US economy, the ongoing bloodshed in Iraq and the low popularity of George Bush, the current president.
But McCain could be their most formidable opponent because he draws support from independent voters.
The Democratic contest has turned into a historic race between Clinton, who is trying to become the first woman to win the White House, and Obama, seeking to become the first black US president.
The two split the early primaries and caucuses. But few delegates were at stake in those contests, which were mostly about building momentum and establishing front-runners.
Starting on Tuesday, the focus will be on the delegate count. A total of 1,681 delegates are at stake for Obama and Clinton in Tuesday's races, and 2,025 delegates are needed to win the Democratic nomination.
With so many states casting votes, Democrats were spending unprecedented amounts of money on television advertising.
Records showed Obama and Clinton each spent $1.3 million last Wednesday and have been increasing their purchases in the days since.
The Northeast was their battleground on Monday, stretching from New Jersey and New York north to Connecticut and Massachusetts.
Apart from Clinton's home state of New York, the polls told a similar story in each, as well as in Missouri and California, with Obama gaining in the polls.
Obama's campaign was eager to claim the underdog's role.
"Senator Clinton is certainly the favourite on February 5, given the huge leads she has held in many of these contests throughout the course of the campaign and the political, historical and geographic advantages she enjoys in many of these states," David Plouffe, Obama's campaign manager, wrote in a memo to reporters.
Phil Singer, a Clinton spokesman, countered that the outcome on Tuesday is "likely to be close due to the proportional allocation of delegates under the Democratic party's rules".
Even so, he said :"We expect to maintain our current overall lead in delegates on February 6."
Given his huge lead in polls, McCain could effectively wrap up the nomination on Tuesday, a remarkable comeback for a candidate whose hopes appeared dashed last year.
A total of 24 US states are holding primaries or caucuses on 5 Feb
It is the day when the largest number of nominating delegates for both Republicans and Democrats are up for grabs
52 per cent of Democratic delegates and 41 per cent of Republican delegates are at stake
Key states include California - with the most amount of delegates for a single state - Georgia, Illinois and New York
Started in 1988 after some southern US states decided to hold primaries simultaenously to boost southern influence in choosing a candidate
McCain projected confidence on Monday, not only about wrapping up the nomination but about next November's general election as well.
"I can lead this nation and motivate all Americans to serve a cause greater than their self-interest," he said while campaigning at a fire station in New Jersey.
Yet many Republicans remain wary of McCain, questioning the senator's conservative credentials because of his reputation as a maverick and his stance backing a path to citizenship for illegal immigrants.
Romney has tried, so far unsuccessfully, to tap into those doubts.
"We're going to hand the liberals in our party a little surprise," boasted Romney, the former Massachusetts governor, predicting he would score an upset in delegate-rich California.
McCain struck back later on Monday with a television ad that showed Romney in a 1994 debate against Democratic Senator Edward M Kennedy, saying he was "an independent during the time of Reagan-Bush. I'm not trying to return to Reagan-Bush".
Unwilling to leave anything to chance, both men hastily rearranged their schedules to make one more late stop in California, the largest prize with 170 delegates.
In the Republican race, there are 1,023 delegates at stake in primaries in 15 states, caucuses in five and the West Virginia state convention.
A candidate needs 1,191 delegates to secure the nomination
So far, McCain has 102 delegates, including endorsements from party leaders who automatically attend the convention. Romney has 93 delegates.
Several states award all their delegates to the winner, and McCain was favoured in New York, New Jersey, Connecticut, Delaware and his home state of Arizona, with 251 delegates combined.
Romney hoped to counter with victories in Utah and West Virginia, as well as in a string of caucuses in Western and Midwestern states.