Sam Querrey will launch the United States' fight to upset holders Spain on their home red clay in the opening Davis Cup semi-final duel against world number five David Ferrer in Gijon on Friday.
Querrey's giant-slaying team-mate John Isner faces Nicolas Almagro in the second rubber of the tie as five-time champions Spain, nicknamed the Armada, aim to reach their second Davis final in a row.
On Saturday, the six-foot-plus American twins Bob and Mike Bryan, the world's top-ranked doubles players, face Marcel Granollers and Marc Lopez, before the reverse singles ties on Sunday.
Spain have dominated the Davis Cup over the past decade, winning it five times, and are surfing a wave of 23 consecutive victories on home soil.
"For us this is probably the biggest test in Davis Cup tennis, perhaps for any country, to come to Spain and beat them on clay," said US captain Jim Courier after the draw on Thursday in Gijon, northern Spain.
Courier's team are hopeful of an upset, having won their last four straight clay-court ties.
"We like our chances," Courier said. "We don't feel like we're the favourites, but we feel like we have a chance and that's the attitude we'll take to the court."
The Americans have lost their last two Davis Cup ties against Spain and they are without the newly retired Andy Roddick, who has been his country's mainstay in the competition over the last decade.
But under the captaincy of former Grand Slam-winner Courier, they have chalked up back-to-back away wins in Switzerland (5-0), where Isner shocked Roger Federer, and France (3-2), where he defeated Jo-Wilfried Tsonga.
"They are players with a very aggressive and powerful style and a way of playing that is very different from ours," Spain's team captain Alex Corretja said of the Americans after the draw.
"We are more resistant. We look more for rhythm and they are going to do quite the opposite."
Spain will have to do without their injured star Rafael Nadal, who continues to rest his troublesome knees on the sidelines, but the USA face two of the best claycourters in world tennis in Ferrer and world number 12 Almagro.
Ferrer in particular has been in fine form lately, with a run to the US Open semi-finals last week, where he lost in four sets to Novak Djokovic.
Spain and the United States are tied at five wins each in their previous 10 Davis Cup meetings.
Ferrer and Querrey have met twice before, winning once each, while Ferrer has won three of his four past games against Isner.
Almagro beat Isner in their only previous tie, at Wimbledon last year, and has won three of his five previous games against Querrey.
The Spaniard said his showdown on Friday with Isner's powerful serve could be key to this weekend's tie.
"We all know how he serves. This year he has won very good matches on clay," Almagro said of his opponent. "We have to be patient and perseverant. We know our chance will come sooner or later."
Isner said: "I am just going to go out there and try to enjoy it. I don't think it is going to be anything I'm not used to."
In the other semi-final, Argentina continue their campaign for a first ever Davis Cup title when they host the Czech Republic in Buenos Aires.