Businessman Donald Trump scored a stunning win over Marco Rubio on the senator's home turf of Florida, pushing him out of the presidential race.
Trump also secured wins in Illinois and North Carolina and is leading in Missouri.
But the Republican front-runner was thwarted in grabbing the day's other major prize - Ohio.
Ohio Governor John Kasich won the Republican presidential primary in his home state, denying Trump a crucial victory, and significantly raising the probability that no candidate will win the GOP nomination outright, and the party will barrel toward its first contested convention since 1976.
Rubio announced that he is suspending his campaign - effectively dropping out.
"After tonight, it is clear that, while we are on the right side, this year we will not be on the winning side," Rubio said.
On the Democratic side, former Secretary of State Hillary Clinton has won four states so far: Ohio, Florida, Illinois, and North Carolina. She was also leading in Missouri.
Illinois was the most recent to be called.
This is shaping up as a dominating night for Clinton - and demoralising one for her rival, Senator Bernie Sanders, who is so far behind in the delegate race that he will need enormous, improbable wins to catch up now.
The Associated Press projected Trump as the winner just after the last polls in Florida's western panhandle closed. Under the rules of Florida's "winner-take-all" GOP primary, Trump will get all 99 of the state's delegates to the GOP convention - his biggest victory of the campaign so far.
Rubio, a first-term senator, had launched his campaign with a message of youth and optimism but he was unable to escape his support for a 2013 effort at immigration reform, which many conservatives believed was too lenient on undocumented immigrants.
And he was unable to escape Trump, who hectored him as "Little Marco," a tool of big donors.
Rubio eventually fired back, trying to fight on Trump's level with insults about the front-runner's tan and his fingers. He also called Trump a "con artist" for his involvement in a "university" that many students said defrauded them.
But Rubio undercut his own message by saying that he would still vote for Trump, were he the nominee.
That odd, mismatched strategy seemed to turn off voters: his poll numbers declined sharply. He won just one state, Minnesota, along with Puerto Rico and the District of Columbia.
Rubio, oddly, mocked the District of Columbia by name in his speech.
"There's nothing more you could have done," Rubio said, speaking in the concourse of a Florida arena - he had rented the whole thing, but the crowd was so small that he only needed a hallway.
"America's in the middle of a real political storm. A real tsunami. And we should have seen this coming."
Even in defeat, however, Rubio could not escape Trump.
A heckler shouted out "Trump for President!" The crowd booed, but Rubio shushed them.
"Don't worry, he won't get beat up at our event," he said, referring to alleged assaults of protestors at Trump events.
Among the Democrats, Clinton's win in Florida is not as decisive: the state's Democratic delegates will be split between Clinton and Sanders, not awarded to the winner en masse.
Still, even before a vote was cast, Clinton already held a commanding lead over Sanders in the delegate race. So far, today's results have extended it.
Trump holds a relatively narrow lead in the overall race for GOP delegates, and needs a very good showing across all five states in order to take a commanding position. If he falters, that would raise the odds of a "contested" GOP convention, where Trump's rivals in the GOP could try to hand the nomination to someone less bombastic, antagonistic and popular.
In early exit polls reported by ABC News, Democratic primary voters had a split view of the two candidates: they tended to see Clinton as far more electable - but see Sanders as more honest.
By a roughly 2 to 1 margin, Democratic voters said Clinton had a better chance than Sanders of beating Trump in a general election matchup across Ohio, North Carolina, Florida, Illinois and Missouri.
But roughly 8 in 10 said Sanders was honest and trustworthy, compared with about 6 in 10 for Clinton. Sanders has dominated among honesty-focused voters all year while Clinton has won those focused on electability by a wide margin.
According to those same early exit polls reported, large majorities of Democrats in Tuesday's primaries would be satisfied with either Clinton or Sanders winning the Democratic nomination. At least 7 in 10 voters across primary voting states would be satisfied with each candidate becoming the party's nominee, with slightly more satisfied with Clinton than Sanders.
Among Republican primary voters, by contrast, preliminary exit polls showed unusual hesitancy about the prospect of Trump as the nominee.
Across all of today's states, a little more than half of GOP voters said they would be satisfied with Trump as the Republican nominee against Clinton, according to early exit polls from ABC News.
Just under four in 10 Republican voters across today's contests said they would consider a third-party candidate if Trump and Clinton were the nominees. Looking specifically at non-Trump supporters, ABC reported six in 10 would consider backing a third-party candidate if Trump became the party's nominee.
FLORIDA (progress counting)
(W) Trump 45.8%, Rubio 27%, Cruz 17.1%, Kasich 6.8%
(W) Clinton 64.5%, Sanders 33.3%
(W) Kasich 47.1%, Trump 35.9%, Cruz 13.2%, Rubio 2.3%
(W) Clinton 56.5%, Sanders 42.7%
NORTH CAROLINA (progress)
Trump 40.3%, Cruz 36.8%, Kasich 12.6%, Rubio 7.7%
(W) Clinton 54.6%, Sanders 40.7%
Trump 38.9%, Cruz 30.5% Kasich 19.6%, Rubio 8.5%
Clinton 50.3%, Sanders 48.9%
Trump 40.8%, Cruz 40.7%, Kasich 10.1% Rubio 6.1%
Clinton 49.6%, Sanders 49.4%
- Washington Post-Bloomberg