Republican presidential frontrunner Donald Trump has scored major wins in the Pennsylvania, Maryland and Connecticut primaries, US networks projected, while Democratic frontrunner Hillary Clinton drew first blood in Maryland.
Trump and Clinton were expected to do well in Tuesday's five contests, which also include votes in Delaware and Rhode Island.
The two are looking to move even closer to locking up the nominations of their respective parties.
Rival Democrat Bernie Sanders' team has sent mixed signals about his standing in the race, with one top adviser suggesting a tough night would push the Vermont senator to reassess his bid and another vowing to fight "all the way to the convention".
Clinton was already looking past Sanders, barely mentioning him during recent campaign events. Instead, she deepened her attacks on Trump, casting the billionaire businessman as out of touch with Americans.
"If you want to be President of the United States, you've got to get familiar with the United States," Clinton said. "Don't just fly that big jet in and land it and go make a big speech and insult everybody you can think of."
Candidates and outside groups have spent $13.9m on advertisements in the states, with Clinton and Sanders dominating the spending.
Sanders said on ABC's "Good Morning America" that his campaign is "handicapped" since the states in play on Tuesday don't allow independents to participate, but added that "we are going to fight through California and then we'll see what happens".
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Democrats are competing for 384 delegates in Tuesday's contests, while Republicans have 172 to win.
Trump is the only one left in the race who can reach the 1,237 delegates needed to secure the nomination before the convention, but he could fall short, pushing the nominating process to the party's July gathering in Cleveland.
Texas Senator Ted Cruz and Ohio Governor John Kasich are now joining forces to try to make that happen.
Their loose alliance marks a shift in particular for Cruz, who has called on Kasich to drop out of the race and has touted the strength of his convention strategy.
Kasich has won just a single primary - his home state - but hopes to sway convention delegates that he is the only Republican capable of defeating Clinton in the general election.
Under their new arrangement, Kasich will not compete for votes in Indiana, allowing Cruz to take Trump on head-to-head in the state's May 3 primary. Cruz will do the same for Kasich in Oregon and New Mexico.