Argentina's Juan Martin del Potro stunned Roger Federer in four sets to reach the US Open semi-finals.
The 24th seed won 7-5 3-6 7-6 (10-8) 6-4 to reach the last four, thrilling his large contingent of supporters in New York.
He goes on to face top seed Rafael Nadal, who earlier beat Russian teenager Andrey Rublev.
Del Potro's victory means Federer and Nadal will end another year having never played each other at the US Open.
Top seed Nadal is now also guaranteed to keep hold of the number one ranking ahead of Federer.
It is the sixth time the pair have been one match from meeting at Flushing Meadows, and their potential semi-final clash had dominated headlines throughout the tournament.
However, an out-of-sorts Federer was no match for Del Potro, who returned 48 hours after his epic five-set win over Dominic Thiem to produce another thrilling victory.
"I honestly was only thinking about tonight," said Federer, 36.
"My head didn't even wander during the match. I knew it was going to be a tough one."
Del Potro, 28, beat Federer to win his only Grand Slam title in New York in 2009, and eight years later he delivered another blow to the 36-year-old on Arthur Ashe Stadium.
"I think I played my best match of the tournament," said the Argentine.
"I played everything well. My serve was good, I hit my forehands as hard as I possibly could.
"This is my home court too. The fans make me feel happy every time I play here. I hope against Rafa the crowd will be cheering for me again."
The Del Potro forehand is among the biggest weapons in the game but his backhand, which has been hampered in recent years after four wrist surgeries, held up superbly.
After the pair split the first two sets with a break apiece, the match turned on a gripping third-set tie-break in which Federer saw four set points slip by.
Del Potro would not be so profligate, hammering a magnificent backhand on his first chance to clinch the set, drawing a huge roar from the Argentine and his supporters high in the stands.
A desperate Federer smash into the bottom of the net drew gasps from the crowd as he offered up a break point at 2-2 in the fourth, which Del Potro snapped up with another blistering backhand return.
Federer's evening ended with him taking evasive action at the net from a massive Del Potro forehand and then swinging a wild volley way over the baseline when threatening to break back.
It was Del Potro's night and, four years after his last Grand Slam semifinal, he closed out the match after two hours and 51 minutes to set up a chance at a second US Open crown.
"I don't know what the turning point was, maybe I got lucky," he said. "I can't believe I am back after all my injuries and surgeries."
The final match statistics were not bad for Federer but he was unexpectedly hesitant, making errors at key moments as he lost his first Grand Slam match of the year.
Having picked up a back injury in the build-up to the US Open, Federer then had to come through two five-set matches in the first two rounds.
"I had struggled too much throughout the tournament to think too far ahead," he said.
"In some ways, I'm actually happy I made the quarters, so I'm not disappointed because it's been a good run this year already.
"Unfortunately I ran into a guy who was better than me today."
Friday's other semi-final will see South Africa's Kevin Anderson take on Spain's Pablo Carreno Busta.