Five-time champion Roger Federer and his French Open-winning compatriot Stan Wawrinka will look to end American hopes in the US Open men's singles at the fourth round stage on Monday.
World number two Federer aims to reach his 11th US Open quarter-final when he tackles American 13th seed John Isner, against who he holds a 4-1 career lead.
Federer, 34, has now reached the fourth round in New York for the 15th year as he looks to return to the final for the first time since 2009.
Isner made the quarter-finals in 2011 and he will hope to maintain American hopes of a first men's champion since Andy Roddick in 2003.
Isner has not dropped serve in 39 games so far at the tournament, a factor which may deter Federer from using his new 'chip-and-charge' on second serve technique.
"At the beginning you try to find the rhythm. Then once you found it, how much do you mix up speeds and slices and big serves, you know, to keep him off balance," said Federer, 34, bidding to become the oldest champion in New York since Ken Rosewall in 1970.
"I tend to like the body serve as well. Sometimes against John maybe that's not a bad play just because he's very long, and if he picks the right side he has long arms so with easy contact he generates a lot of power."
If Isner falls, then home hopes will rest with Donald Young, the great underachiever of American tennis.
He faces fifth seeded Wawrinka, a semi-finalist in 2013.
Young, ranked 60, has twice come back from two sets to love down at the tournament, to beat French 11th seed Gilles Simon in the first round and then Serb 22nd seed Viktor Troicki in the third.
Young defeated Wawrinka in New York in the second round in 2011 in a fifth-set tie-break.
In the other fourth-round matches, third seed and 2012 champion Andy Murray, who has advanced to the quarter-finals or better at his last 18 Grand Slams, faces South Africa's 15th seed Kevin Anderson.
Anderson has never gone beyond the fourth round at a major and trails Murray 4-1 in career meetings, including two clashes this year.
Czech sixth seed Tomas Berdych and French 12th seed Richard Gasquet meet in the other last-16 clash with both men having a previous run to the semi-finals under their belts.
In the women's last-16, two-time runner-up Victoria Azarenka, seeded 20 after an injury-hit campaign, tackles Uzbekistan-born American Varvara Lepchenko.
Azarenka, the runner-up to Serena Williams in 2012 and 2013, holds a 3-1 lead over Lepchenko winning their most recent meeting on grass in Birmingham in June.
Two-time Wimbledon champion Petra Kvitova, the Czech fifth seed, faces Britain's Johanna Konta who is bidding to become the first qualifier to reach the quarter-finals since America's Barbara Gerken in 1981.
Australian 22nd seed Samantha Stosur, the champion in 2011 and the last woman to beat Serena in New York, tackles Italy's Flavia Pennetta, who is chasing a place in the quarter-finals for the sixth time.
Romanian second seed Simona Halep, who has made at least the quarter-finals of all the Slams with the exception of the US Open, looks to correct that against 2013 Wimbledon runner-up Sabine Lisicki of Germany.