Ghana, Africa's sole representative in the last 16, are banking on having the whole continent behind them in Rustenburg on Saturday - and they will need it.
Bob Bradley's American squad never seem to know when they are beaten - as they proved time and again in the group stage.
The USA looked doomed to an early exit, until Landon Donovan struck in the 91st minute of their Group C finale against Algeria to secure the 1-0 victory that clinched their place in the last 16 as section leaders.
It was the only time they have led in a match so far at South Africa 2010, having come from behind to snatch a 1-1 draw against England and having trailed 2-0 to Slovenia before grabbing a point.
Bradley said: "These guys never give up. I was worried because we could have gone away empty-handed, but my players decided otherwise and never stopped believing. We're proud to finish first in the group on five points and we're already prepared to go further."
The Americans, who will have striker Robbie Findley available again after suspension, have the never-say-die attitude to make the quarter-finals - but they will face a talented Ghana outfit who are fired up as the only African team left in the tournament for the second successive Finals.
Black Stars midfield player Stephen Appiah said: "It means a lot to repeat what we did in 2006, when we were the only African team to qualify for the last 16, and I think we can do better.
"As we are the only African team left in the competition, we are going to get all the support in the stadium, as we have done Africa proud."
Appiah does not believe that the USA will prove more beatable opponents than England, who were pipped for top spot in Group C on goals scored.
"There is no easy game," stressed the Bologna midfielder. "If you are talking about all the teams, some of them have big stars, so there is no easy team. All the teams who qualified are strong - that's why they qualified."
Ghana beat the USA 2-1 in the 2006 Finals at the group stage, but they will need to find their touch in front of goal if they are to repeat that victory. So far their two goals at South Africa 2010 have been penalties from Asamoah Gyan.