Jannik Sinner attempts to reach a maiden US Open semi-final on Wednesday as fellow world number one Iga Swiatek hopes to stem an American championship surge.
Sinner is the only top-four player left in the men's draw following the exits of Novak Djokovic, Carlos Alcaraz and Alexander Zverev.
However, he is yet to reach the last-four in New York and faces a test of his credentials against fifth-ranked Daniil Medvedev, the 2021 US Open champion.
Sinner defeated Medvedev from two sets down to win his first major at the Australian Open in January before the mercurial Russian avenged that loss at Wimbledon.
"I will try to think more about Wimbledon than the Australian Open," said Medvedev, also the 2019 and 2023 runner-up at the US Open.
"Against Jannik, I feel like in a way we know our game, what we will try to bring to the table, and then it comes to always a moment's deuce, breakpoint, maybe try to surprise him or not, what he will do, what I will do."
Victory would give Medvedev a place in a 10th Grand Slam semi-final.
The winner of that quarter-final will face either Australia's 10th-ranked Alex de Minaur or Britain's Jack Draper, the world number 25.
Left-handed Draper is into his first Grand Slam quarter-final and is the first British man to make the last eight in New York since Andy Murray in 2016.
Draper has not dropped a set over four rounds, winning 47 of 48 service games and saving 20 of 21 break points.
"I just need to keep going," Draper said. "I have great people around me and I love playing here in New York... I love playing on the big stage."
De Minaur is also looking to reach his first Grand Slam semi-final and is playing in his first tournament since a hip injury forced him to hand Djokovic a walkover in the Wimbledon quarter-finals.
If the Australian achieves his 50th Grand Slam match win, he would become the first from his country to reach the US Open semi-finals since Lleyton Hewitt in 2005.
With Frances Tiafoe and Taylor Fritz already lined up for an all-American men's semi-final on Friday, and Emma Navarro safely into the women's last four, home fans are dreaming of a title sweep this weekend.
Swiatek eyes title
Andy Roddick was the last US man to lift a Grand Slam singles trophy in New York in 2003 while Serena Williams, Sloane Stephens and Coco Gauff have triumphed in the women's tournament in the last decade.
Jessica Pegula will attempt to become the fourth American player in the semi-finals.
However, she has the tricky task of taking on world number one and 2022 champion Swiatek, the four-time French Open winner who is seeking a sixth Grand Slam title.
Swiatek boasts a 6-3 career edge over the sixth-ranked Pegula who has fallen short in six Grand Slam quarter-finals.
Poland's Swiatek defeated Pegula in the quarter-finals in 2022 on her way to the US Open title.
Wednesday's other quarter-final sees Brazilian world number 21 Beatriz Haddad Maia face unseeded Karolina Muchova of the Czech Republic.
A semi-finalist 12 months ago, Muchova then suffered a serious wrist injury which sidelined her until June this year.
A former top 10 player now ranked at 52, Muchova has yet to drop a set, knocking out two-time champion Naomi Osaka and this year's French Open and Wimbledon runner-up Jasmine Paolini.
Left-hander Haddad Maia, a semi-finalist at Roland Garros last year, is the first Brazilian woman to reach the quarter-finals in New York since Maria Bueno in 1968.