Republican Donald Trump and Democrat Hillary Clinton face another opportunity to pull away from their rivals in the so-called Super Tuesday primaries, their biggest test yet.
It will be a delegate -rich dash across the country that could accelerate their march toward the general election on November 8.
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Voters from Vermont to Colorado, Alaska to American Samoa and several states in between are heading to polling places and caucus sites on the busiest day of the 2016 primaries.
The first polls opened in Vermont at 5am (10:00 GMT) and the final polls were due to close 19 hours later in Alaska.
For the Democrats, it is a straight battle between former Secretary of State Clinton and Vermont Senator Bernie Sanders. After her landslide win in South Carolina, Clinton has a strong lead over Sanders with 548 delegates to his 87, according to the Associated Press.
She went into Super Tuesday with a big lead in six southern states with high numbers of African American voters.
For her rival, Sanders, the challenge is to outperform Clinton in states where he has seen a surge of support from young, white, independent-minded voters, including in Minnesota and Massachusetts.
"I just feel like it's that point in American history where we only have this opportunity once - to have a president who can actually make change, real change," Jesse Clark, a Sanders supporter attending his Tuesday rally in Vermont, told Al Jazeera.
"I know there's a lot of talk and a lot of politics being thrown around, but here's somebody who spent his whole adult life trying to make people's lives like mine, my family's, better."
High-stakes election
It is a more crowded race in the Republicans' camp, with property tycoon and reality TV star Trump, Texas Senator Ted Cruz, Florida Senator Marco Rubio, retired neurosurgeon Ben Carson and Ohio Governor John Kasich all battling for the party nomination.
The contests come at a turbulent moment for Republicans as they grapple with the prospect of Trump becoming the party's nominee.
Rivals Rubio and Cruz are engaged in a frantic effort to stop the billionaire - with Rubio in particular lobbing surprisingly personal attacks - but it is unclear whether they have made their move too late.
"If we nominate him [Trump], let me just tell you a vote for Donald Trump tomorrow is literally a vote for Hillary Clinton in November and it cannot happen," said Florida Senator Rubio at a campaign event in Jenks, Oklahoma, on Monday.
Texas Senator Cruz attacked Trump's position on illegal immigrants. The businessman has called for deporting all illegal immigrants and has said he would get the Mexican government to pay for the building of a wall along the US-Mexico border.
Cruz said Trump should clarify comments made to the New York Times following reports from news website BuzzFeed which said Trump had suggested to the Times' editorial board in an off-the-record briefing on January 5 that he would most likely not stand by his immigration proposals if elected president.
The Texas senator also attacked Trump's past campaign donations at an event in Houston.
"You don't get to fund open-border Democrats for four decades and then suddenly when you run for president discover and announce you're for securing the border," Cruz said.
The Texas senator's event was interrupted numerous times by protesters chanting "Cruz, bad for Texas, bad for the country." He called the first display of protesters "Bernie Sanders supporters" but after several interruptions the demonstrators were removed.
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Clinton told reporters in Minneapolis on Tuesday that the Republican candidates are "now running their campaigns based on insults. It's turned into a kind of one-upmanship on insulting".
Opinion polls showed Trump was likely to consolidate his status as favourite to win the Republican nomination.
Al Jazeera's Alan Fisher, reporting from Stafford, Texas, said the Trump bandwagon continued to gain momentum.
"He [Trump] knows that historically the person who wins most states on Super Tuesday for the Republicans goes on to win the nomination. So it is a big day for the Republican party, a big day for all the candidates after the nomination but it can also be a big day, a huge day, for Donald Trump."
On Super Tuesday, 595 delegates are at stake for Republicans. For Democrats, there are 1,004.
Considering Republican candidates need 1,237 delegates to win the party's nomination, and Democrats need 2,383, Super Tuesday is one of the most important days in the US presidential election.
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