Serena Williams, chasing a calendar Grand Slam, seeks a US Open quarter-final spot that could be against her sister Venus while top-rated Novak Djokovic also tries to advance on Sunday.
Top-ranked Serena needs only four more triumphs to complete the first calendar Slam since Steffi Graf in 1988.
Williams, holder of all four major titles, also seeks her 22nd career Slam singles crown to match Graf's Open Era record.
But tension has mounted at Arthur Ashe Stadium as Williams has struggled through her past two matches, battling to keep her focus early before finding her top form with her formidable serve.
"I'm not trying to live on the edge," said Williams, who is 10-0 in three-setters at Grand Slams this year.
Serena, 33, will face US 19th seed Madison Keys while sister Venus, 35, takes on 152nd-rated Estonian qualifier Anett Kontaveit.
If the siblings both win, it will set up their 27th career meeting on Tuesday and their fifth at the US Open, with Serena holding a 15-11 all-time edge after winning their most recent match in July at the fourth round of Wimbledon.
They are 2-2 on the New York hardcourts, each with a finals win over the other.
But Keys is happy to have a chance to foil Serena's quest for history.
"I would be OK with it," Keys said. "What am I going to say? I want her to beat me?
"I want to go out and I want to win. I mean, obviously it's a big story. She has won four in a row and she's going for the calendar year. That's great, but at the same time I want to win. So I'd be OK with beating her, yeah."
Williams beat Keys in this year's Australian Open semi-finals.
"Getting that first win is really big for me against her, but it's also first time in the fourth round at the US Open. It's just icing on the cake," Keys said.
"She's one of the greatest tennis players ever. You can sit there and watch every single match she's ever played. I don't think you can be like, 'OK, that's a big weakness.' If that was possible she wouldn't be going for her calendar-year Slam."
Other women's last-16 matches on Sunday send Russian 13th seed Ekaterina Makarova against France's Kristina Mladenovic and Canada's 25th-seeded Eugenie Bouchard against Italy's Roberta Vinci.
Officials were waiting for confirmation that Bouchard would indeed play her match after she withdrew from women's and mixed doubles Saturday following a fall in the locker room late on Friday that gave her a head injury.
US Open medical staff suggested she not play doubles and were treating and examining Bouchard to determine match fitness late on Saturday.
Bouchard lost to Vinci 6-1, 6-0 in New Haven two weeks ago in their only meeting.
On the men's side, Djokovic will open the night session at Arthur Ashe Stadium against Spain's 23rd-seeded Roberto Bautista Agut while defending champion Marin Cilic, the ninth seed from Croatia, faces 27th-seeded Frenchman Jeremy Chardy in the morning opener on Ashe.
Cilic or Chardy will play for a last-eight date with a Frenchman, either 19th seed Jo-Wilfried Tsonga or Benoit Paire, while the Djokovic-Bautista Agut winner will meet either Spain's Feliciano Lopez or Italy's Fabio Fognini next.
It was Fognini who rallied from two sets down to eliminate 14-time Grand Slam champion Rafael Nadal in a third-round matchup.