Former champions Rafael Nadal and Novak Djokovic will bid to set up a 53rd meeting with victories in the US Open semi-finals on Friday.
The pair have met more than any two men in the Open era and could meet for a fourth time in a final in New York.
Spanish defending champion Nadal faces Argentine third seed Juan Martin del Potro in the last four at 21:00 BST as he aims for an 18th Grand Slam title.
Two-time winner Djokovic follows against Japan’s Kei Nishikori.
Nadal and 2009 US Open champion Del Potro have met twice in Grand Slams this year, at the French Open and Wimbledon, with Nadal winning on both occasions.
But the world number one has spent nearly four hours longer on court than Del Potro at Flushing Meadows, including a gruelling four-hour 49-minute marathon against Dominic Thiem in the quarter-finals.
“It will be a very tough one,” three-time US Open winner Nadal said.
“At Wimbledon he’s a great player, he’s a great player everywhere. But the challenge of playing him on hard courts, of course, is even higher for me personally.
“I know that I will have to play at my highest level to keep having chances of success. I am focused on trying to make that happen.”
The pair’s meeting at Wimbledon in the quarter-finals lasted almost five hours with Nadal winning a thrilling fifth set.
“It could be another big battle, as the Wimbledon match was,” Del Potro said.
“Of course, I like to play always with the number one of the world, it doesn’t matter the tournament or the conditions.
“I just have the chance to play the greatest in this sport, and it’s amazing for me.”
Djokovic still going in ‘toughest’ US Open
Djokovic is aiming for a 14th Grand Slam title, which will take him level with American Pete Sampras in third in the men’s all-time list.
Temperatures have soared during the tournament and the Serb says the conditions have been the “toughest” he has faced at Flushing Meadows.
He has beaten 21st seed Nishikori in the pair’s past 13 encounters but lost their only meeting at the US Open, as Nishikori reached his only Grand Slam final in 2014.
“For sure it [the 2014 win] is going to give me good confidence, even though I didn’t remember,” Nishikori said.
“Maybe I will try to watch the match again.
“I don’t have a great record against Novak, but always it’s been a tough match the last couple of years.
“I’ve seen a chance, but I haven’t been able to make the last step.”