Roger Federer and Maria Sharapova crashed out of the US Open on Monday in back-to-back seismic shocks under the Arthur Ashe Stadium lights.
Federer, the five-time champion and looking to end his 10-year wait to add to his total in New York, was beaten by Australia's world number 55 John Millman 3-6, 7-5, 7-6 (9/7), 7-6 (7/3).
It was 20-time major winner Federer's first loss against a player outside the top 50 in 41 meetings at the US Open.
"It was very hot. I felt I couldn't get any air and I was sweating more and more and became more and more uncomfortable," explained Federer. "I guess I was happy when the match was over."
He added: "John dealt with it better -- he's from Brisbane, one of the most humid places in the world!"
It was the world number two's earliest defeat at the tournament since a fourth round loss to Tommy Robredo in 2013.
The result meant there would be no quarterfinal showdown with old rival Novak Djokovic who will now face Millmann instead.
"I have so much respect for Roger and everything he's done for the game. He's been a hero of mine," said Millman.
"Today he was definitely not at his best. But I'll take it."
Sharapova, the 2006 champion, suffered a second successive last-16 exit in New York, blasted off court by Carla Suarez Navarro.
The Spanish player marked her 30th birthday in style with a memorable 6-4, 6-3 win over the five-time major champion whose last Slam title was in Paris in 2014.
Djokovic reached the quarterfinals with a 6-3, 6-4, 6-3 victory over unseeded Joao Sousa.
Djokovic said he was relieved to get past 68th-ranked Sousa in straight sets as temperatures soared again.
"Very happy to get this one done in straight sets," said Djokovic, who left the court for a medical evaluation early in the third set but returned to wrap things up in exactly two hours.
Marin Cilic, seeded seven, beat David Goffin of Belgium 7-6 (8/6), 6-2, 6-4 and next takes on Japan's Kei Nishikori who saw off German veteran Philipp Kohlschreiber 6-3, 6-2, 7-5.