Sam Querrey will launch the US 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 Rob and Mike Bryan, the top-ranked doubles players in the world, face Marcel Granollers and Marc Lopez, before the return singles ties on Sunday, according to the draw made in Gijon, northern Spain, on Thursday.
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.
But they will have to do without their injured star Rafael Nadal, who continues to rest his troublesome knees on the sidelines.
US team captain Jim Courier has called the trip to Spain the toughest mission in the Davis Cup but his team are hopeful of an upset having won their last four straight clay-court ties.
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.