The US Open quarter-finals begin on Tuesday with ex-champion Naomi Osaka hunting a last-four berth and Germany's Alexander Zverev seeking to exploit Novak Djokovic's shock elimination.
Osaka, the 2018 US Open winner, takes on unseeded American Shelby Rogers under the lights at Arthur Ashe Stadium for a place in the semi-finals.
The winner will play either Kazakhstan's 23rd seed Yulia Putintseva or 28th-seeded American Jennifer Brady for a spot in this weekend's final.
"Of course, it's going to be challenging. She's in the quarters of a slam. She's a great player," the 22-year-old Osaka, seeded fourth, said of Rogers.
The 27-year-old Rogers will be featuring in the quarter-finals at Flushing Meadows for the first time.
Her appearance comes two years after her career was plunged into uncertainty when she ruptured cartilage in her knee at Indian Wells.
In the men's draw, fifth seed Zverev lines up against Croatia's 27th seed Borna Coric for a spot in the last four.
The winner will take on either 12th seeded-Canadian Denis Shapovalov or Spain's Pablo Carreno Busta, who also play on Tuesday.
Carreno Busta advanced to the quarters by default on Sunday after Djokovic was disqualified for accidentally hitting a line judge when he smacked the ball in frustration.
His departure blew the tournament wide open and means it will produce a first-time Grand Slam winner in the men's competition this year.
"Now it gets interesting," Zverev said Sunday after bulldozing Spain's unseeded Alejandro Davidovich Fokina to reach the quarters.
"It's going to be one of the young guys," who wins, he added.
In the two other men's quarter-finals, to be played on Wednesday, second seed Dominic Thiem plays 21-year-old Australian Alex de Minaur and third seed Daniil Medvedev takes on his tenth seed compatriot Andrey Rublev.
Third seed Serena Williams plays unseeded Bulgarian Tsvetana Pironkova in one of the other women's quarters on Wednesday.
Williams is aiming for a record-equalling 24th Grand Slam title this week.
Results from US Open tennis championship in New York on Monday (x-denotes seed)
Men's singles
Fourth round
Andrey Rublev (RUS x10) bt Matteo Berrettini (ITA x6) 4-6, 6-3, 6-3, 6-3
Alex De Minaur (AUS x21) bt Vasek Pospisil (CAN) 7-6 (8/6), 6-3, 6-2
Dominic Thiem (AUT x2) bt Felix Auger-Aliassime (CAN x15) 7-6 (7/4), 6-1, 6-1
Daniil Medvedev (RUS x3) bt Frances Tiafoe (USA) 6-4, 6-1, 6-0
Women's singles
Fourth round
Tsvetana Pironkova (BUL) bt Alize Cornet (FRA) 6-4, 6-7 (5/7), 6-3
Serena Williams (USA x3) bt Maria Sakkari (GRE x15) 6-3, 6-7 (6/8), 6-3
Victoria Azarenka (BLR) bt Karolína Muchová (CZE x20) 5-7, 6-1, 6-4
Elise Mertens (BEL x16) bt Sofia Kenin (USA x2) 6-3, 6-3