A very strong showing in primaries in Connecticut, Delaware, Maryland, Pennsylvania and Rhode Island would Clinton on the cusp of Democratic victory, a monumental step in her quest to become the nation's first female commander in chief.
"I don't have the nomination yet," the former secretary of state said in a town hall event in Philadelphia, Pennsylvania's largest city, on the eve of the vote. "We're going to work really hard until the polls close tomorrow."
Trump also was expected to extend his formidable lead in the bruising race for the Republican nomination, even as rivals Ted Cruz and John Kasich mounted a hasty, and already fraying tag team effort to try to block him.
Kasich agreed to forego campaigning in Indiana, a winner-take-all state that votes May 3, and Cruz will return the favor later in New Mexico and Oregon.
But within hours of the surprise deal, the Ohio governor was already playing it down, saying he was not telling his supporters in Indiana not to vote for him. "What's the big deal?" he said.
- 'Experience and wisdom' -
Tuesday's voting began at 6 am in Connecticut and one hour later in the other states. Polls across all five states close at 8 pm.
Voting was brisk in Maryland. "So far it looks good," said Lucy Freeman, 79, a Democratic precinct chair at a voting station in Chevy Chase, Maryland.
New US citizen Imalka Senahidra, a 53-year-old born in Sri Lanka, was voting for the first time and nervous about "which way the country might go."
"I've always believed in experience and wisdom, so I'll go along with that," she said.
Clinton was favored to win all five state Democratic contests, with polls giving her a double-digit lead over rival Bernie Sanders in Pennsylvania, the biggest state of the bunch with 189 delegates.
Big wins on Tuesday night would put her within striking distance of the Democratic nomination, piling up pressure on Sanders, who has vowed to fight on until the California primary June 7.
"I don't accept there is no path forward. Let's not count our chickens before they're hatched," Sanders said Tuesday in an interview with MSNBC.
"There are five contests today. The state of California — last I heard the largest state in the United States of America — has not yet cast a ballot," he said.
Sanders has deflected questions about whether he would actively support a Clinton candidacy if she is the nominee, suggesting it was up to her to win over his passionate young followers.
- 'Pathetic' plan -
Trump, meanwhile, was in full attack mode, pouring scorn on the Cruz-Kasich deal as an act of a political desperation. "You know if you collude in business, or you collude in the stock market, they put you in jail," Trump boomed in Warwick, Rhode Island.
"But in politics, because it's a rigged system, because it's a corrupt enterprise, in politics you're allowed to collude." The partnership "shows how weak they are," Trump said. "It shows how pathetic they are."
Cruz told potential voters in Indiana Monday that the deal would give them "a straight and direct choice between our campaign and Donald Trump."
According to a recent CBS poll, Trump leads Indiana with 40 percent of likely Republican voters, compared to 35 percent for Cruz and 20 percent for Kasich. A Trump loss in Indiana would make it much harder for him to gain the 1,237 delegates needed to win the nomination in the first round of balloting at the party's convention in Cleveland July 18-21.
If he falls short, Trump runs the risk that his delegates, most of whom are bound to vote for him in only the first round of balloting, will desert him in subsequent rounds. Cruz in particular has been successfully maneuvering in state party conventions to have individuals named to delegate slots who, though initially bound to Trump, would be sympathetic to Cruz in later rounds once free to vote for whomever they choose.
Party heavyweights, alarmed by the prospect of a Trump nomination, have long pressed for a united effort around a single candidate against him.
But Cruz is almost as unpopular with the party's establishment as Trump, and Kasich has refused to bow out even though he has only won his home state of Ohio.
The Texas senator, meanwhile, has put out word that he has begun weighing possible running mates, including former White House hopeful Carly Fiorina.