Venus Williams will be the sentimental favourite when the 37-year-old takes on Sloane Stephens in one semi-final before Madison Keys battles it out with CoCo Vandeweghe in the other.
It is the first time since Wimbledon 1985 that four American women have featured in a grand slam semi-finals, and the first time since 1981 at the U.S. Open.
A trip to Saturday's final and perhaps a third U.S. Open crown 16 years after she last hoisted the trophy would cap a renaissance season for the ninth seeded Williams that has also seen her make the finals at the Australian Open and Wimbledon.
For everyone else it will be a new pressure-packed experience as they make their maiden appearances in the Flushing Meadows semi-finals.
News that makes sense
Your trusted source for staying up-to-date with the world around you. Get free daily news updates and analysis, straight to your inbox.
No player was more surprised to find themselves in the last four than Stephens, who just six weeks ago was ranked outside the top 950 in the world.
Sidelined for almost a year after undergoing foot surgery, Stephens returned at Wimbledon and has been on a tear ever since, knocking off 11th seed Dominika Cibulkova, 30th seed Julia Goerges and 16th seed Anastasija Sevastova en route to the final four.
The other semi will see Keys, another player making a surprising run for the title after coming back from injury, going up against Vandeweghe in a battle of big-hitters.
Keys, who missed the first two months of the season recovering from wrist surgery, is peaking at the right time and blazed into the her semi-final with a 69 minute 6-3 6-3 dismantling of Estonia's Kaia Kanepi.
Vandeweghe, meanwhile, underlined her contender status by taking down world number one Karolina Pliskova in straight sets.
The two players have met twice already this season with Keys winning both times.
(Reporting by Steve Keating. Editing by Nick Mulvenney)
