The last time the Welsh were on this stage they were knocked out by a prodigious talent named Pele, but they have been making waves at major tournaments more recently and will be looking to get their campaign off to a winning start.
USA were also absent from the last World Cup and so they too will want to make up for lost time in a group which has already seen England put down a marker with a big win over Iran.
Here, Sports Mole compares both squads to see how they stack up against each other ahead of the contest.
USA
Most valuable player:
Christian Pulisic (£33m)
Overall squad value:
£241m
Most capped player:
DeAndre Yedlin (75)
Leading goalscorer:
Christian Pulisic (21)
Total caps:
685
Total goals:
82
Oldest player:
Tim Ream (35)
Youngest player:
Yunus Musah (19)
Average age:
25.2
SQUAD IN FULL
Goalkeepers: Matt Turner (Arsenal), Sean Johnson (New York City FC), Ethan Horvath (Luton Town)
Defenders: DeAndre Yedlin (Inter Miami), Tim Ream (Fulham), Walker Zimmerman (Nashville SC), Aaron Long (New York Red Bulls), Antonee Robinson (Fulham), Sergino Dest (AC Milan), Shaq Moore (Nashville SC), Cameron Carter-Vickers (Celtic), Joe Scally (Borussia Monchengladbach)
Midfielders: Kellyn Acosta (Los Angeles FC), Weston McKennie (Juventus), Tyler Adams (Leeds United), Cristian Roldan (Seattle Sounders), Brenden Aaronson (Leeds United), Yunus Musah (Valencia), Luca de la Torre (Celta Vigo)
Forwards: Christian Pulisic (Chelsea), Jordan Morris (Seattle Sounders), Tim Weah (Lille), Josh Sargent (Norwich City), Jesus Ferreira (Dallas), Giovanni Reyna (Borussia Dortmund), Haji Wright (Antalyaspor)
WALES
Most valuable player:
Brennan Johnson (£17.4m)
Overall squad value:
£139.1m
Most capped player:
Chris Gunter (109)
Leading goalscorer:
Gareth Bale (40)
Total caps:
990
Total goals:
92
Oldest player:
Wayne Hennessey (35)
Youngest player:
Rubin Colwill (20)
Average age:
26.4
SQUAD IN FULL
Goalkeepers: Wayne Hennessey (Nottingham Forest), Danny Ward (Leicester City), Adam Davies (Stoke City)
Defenders: Neco Williams (Nottingham Forest), Ben Davies (Tottenham Hotspur), Ben Cabango (Swansea City), Joe Rodon (Rennes, on loan from Tottenham Hotspur), Chris Mepham (Bournemouth), Ethan Ampadu (Spezia, on loan from Chelsea), Chris Gunter (AFC Wimbledon), Connor Roberts (Burnley), Tom Lockyer (Luton Town)
Midfielders: Aaron Ramsey (Nice), Joe Allen (Swansea City), Harry Wilson (Fulham), Joe Morrell (Portsmouth), Dylan Levitt (Dundee United), Rubin Colwill (Cardiff City), Jonny Williams (Swindon Town), Matthew Smith (Milton Keynes Dons), Sorba Thomas (Huddersfield Town)
Forwards: Gareth Bale (Los Angeles FC), Dan James (Fulham, on loan from Leeds United), Kieffer Moore (Bournemouth), Mark Harris (Cardiff City), Brennan Johnson (Nottingham Forest)