McCain could be the most formidable opponent for Clinton or Obama because he draws support from independent voters.
The 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.
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.
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.
"None of us really understands what the impact of all these contests on one day will be for for any of us," Clinton said on ABC's Good Morning America programme.
Obama said that he did not expect either of them to come out on top on Tuesday
"No matter what happens I think we'll see a split decision," he said.
Clinton voted in suburban New York, accompanied by her husband, former President Bill Clinton. Obama headed back to Illinois after a round of television and radio interviews.
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 making gains on his rival.
"The fact that we've made so much progress I think indicates that we've got the right message," Obama said on NBC's Today show.
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.
He has commanding double-digit leads in New York and New Jersey as well as many other of the largest states.
"We're going to win today, we're going to win the nomination and we're going to win the presidency," McCain told a crowd of several hundred at an early morning rally at New York's Rockefeller Centre.
A total of 24 US states are holding primaries or caucuses on Feb 5
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
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 California, which has 170 delegates.
A new Reuters/C-SPAN/Zogby poll showed Romney leading McCain by seven points in California.
Mike Huckabee, the former Arkansas governor, who was hoping to get his campaign back on track with a strong showing in the south, took the first contest of the day winning in West Virginia.
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.
Source: Al Jazeera and agencies