Christian Pulisic, John Brooks and Timothy Chandler will face Mexico for the first time in Friday night's World Cup qualifier.
All three were named in Jurgen Klinsmann's starting lineup for the game in Columbus, Ohio, in what appears to be switch to a 3-5-2 formation that includes Timmy Chandler and Fabian Johnson on the wings of three center-backs: Matt Besler, John Brooks and Omar Gonzalez.
Pulisic, 18, starts in the third straight game for the U.S. after only making his senior debut in March -- also at MAPFRE Stadium in a 4-0 win against Guatemala.
Brooks will play in his first World Cup qualifier, though he has 27 caps and previously played in the 2014 World Cup in Brazil.
Chandler also has 27 caps, with his first coming in 2011, but he has never played against the Americans' biggest rivals.
DeAndre Yedlin and Alejandro Bedoya are notable midfielders on the bench, with Klinsmann instead giving the nod to Pulisic, Johnson, Michael Bradley and Jermaine Jones.
Jones only returned to the Colorado Rapids' starting lineup on Sunday after tearing a knee ligament on July 4.
Mexico coach Juan Carlos Osorio puts out an attack-heavy lineup featuring Carols Vela, Javier Hernandez and Giovani dos Santos.
Rafa Marquez, 37, starts at center-back and becomes the first Mexico player to feature in four World Cup qualifiers in the United States.
The full U.S. lineup:
Goalkeeper: Tim Howard
Defenders: Matt Besler, John Brooks, Omar Gonzalez
Midfielders: Fabian Johnson, Michael Bradley, Jermaine Jones, Christian Pulisic, Timothy Chandler
Forwards: Bobby Wood, Jozy Altidore
The full Mexico lineup:
Goalkeeper: Alfredo Talavera
Defenders: Diego Reyes, Rafa Marquez, Hector Moreno, Miguel Layun
Midfielders: Andres Guardado, Hector Herrera, Giovani dos Santos, Jesus Corona
Forwards: Carlos Vela, Javier Hernandez