Democrat Mrs Clinton and Republican Mr Trump hold sizeable leads in all five contests, according to recent polling.
Mr Trump's rivals have already shifted focus away from the north-east.
Ted Cruz and John Kasich have teamed up to help each other in the Indiana, Oregon and New Mexico primaries.
Mr Trump has condemned their pact as a sign of weakness and desperation.
On Tuesday, the Republican frontrunner also fired back at celebrities who said they would leave for Canada if he was elected, including Lena Dunham, the actress and creator the television series Girls.
"Well she's a B actor and, you know, has no mojo," he said. "I heard Whoopi Goldberg said that too. That would be a great, great thing for our country."
Analysis: Anthony Zurcher, BBC North America reporter
After a setback in
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Hillary Clinton and Donald Trump are poised for a dominating showing in one of the last multi-state primary days of the 2016 presidential campaign.
Last week in New York the two front-runners reasserted themselves after a string of stumbles both at the ballot boxes and in the headlines. This week they could consolidate their position at the top - or more.
It's hard to imagine a scenario where Democrat Mrs Clinton doesn't have the nomination sewn up by Wednesday morning. She is in Philadelphia on Tuesday and might want to check out hotel suites near the site of July's Democratic National Convention.
Republican Mr Trump's path to his party's nomination remains more uncertain - but a strong result on Tuesday will edge him ever-closer to the magic 1,237 delegate mark and make wresting the prize from his grasp all the more difficult.
It looks like Mr Trump's poor showing in Wisconsin three weeks ago was just a blip and not evidence of a campaign in decline. It proved that if the political stars aligned - united Republican opposition, a hostile local media and a string of mis-steps by the Trump team - the New Yorker is beatable. To the despair of the #NeverTrump forces, however, those circumstances may not appear again.
Read more on the US election
Which states are voting?
Connecticut, Delaware, Maryland, Pennsylvania and Rhode Island are holding primaries on Tuesday.
In the Republican race, the candidates are focused on blocking Mr Trump from gaining 1,237 delegates and so forcing a contested convention this July in Cleveland.
That would mean party delegates - Republican officials and activists - choose the nominee.
The hope of a contested convention is keeping Mr Kasich and Mr Cruz in the race. Both candidates have no chance of securing the nomination outright.
Meanwhile, Democrat Bernie Sanders is pushing hard for a win in Rhode Island, where Mrs Clinton's lead is slimmer. He is also hoping for an upset in Pennsylvania, with its many working-class voters.
However, after Tuesday's results, it is unlikely Mr Sanders will be able to overcome Mrs Clinton's lead to become the Democratic nominee for president.
Mrs Clinton is on the rebound after winning the
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Why is Mrs Clinton favoured to win?
In a word, demographics. Mrs Clinton does best in races where the electorate is diverse, older or affluent. The north-eastern voters are all of those things.
With a large African-American population and one of the highest average household incomes in the country, Maryland represents a daunting challenge for the Sanders campaign.
Pennsylvania seemed like more fertile ground for Mr Sanders because it looks somewhat like Michigan, a blue-collar state that his campaign won. However, polls show Mr Sanders trailing badly even in Pennsylvania.
Mr Trump is winning over voters but not necessarily fellow
Republicans
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What's the deal with Pennsylvania's Republican delegates?
It's complicated. Pennsylvania awards its 71 delegates by a state-wide vote and by congressional district.
Heavily favoured to win the popular vote, Mr Trump should easily gain the 17 state-wide delegates.
However, the 54 delegates awarded by congressional district are "unbound" or free to support the candidate of their choice regardless of the outcome of the popular vote.
Before the convention, Mr Cruz and Mr Kasich will be lobbying these delegates, hoping to gain their allegiance.
Mr Cruz is campaigning heavily in
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Is the Cruz-Kasich pact already unravelling?
The pact itself is very narrowly focused.
Mr Kasich is to give Mr Cruz a "clear path" by not campaigning in Indiana. Mr Cruz will reciprocate in New Mexico and Oregon.
But neither has endorsed tactical voting among their supporters. And Mr Kasich said after the pact was announced that voters in Indiana "ought to vote for me".
No other states are included and both campaigns intend to fight for their candidate should there be a contested convention, not to mention how far apart the pair are on policy.
Is it finally over after Tuesday?
Yes and no. On the Democratic side, Mrs Clinton might have essentially wrapped up the race if she stretches her lead.
Mr Sanders will probably shift his focus from competing outright with Mrs Clinton to trying to push the Democratic Party platform further to the left. If he does well in coming primaries like California and New Jersey, he will have more leverage.
The Republican race is a lot more fluid. If Mr Trump performs as expected on Tuesday, the Stop Trump movement will make its final stand.
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