The U.S. has been in Azteca before with the chance to make history and beat Mexico, but each and every time has fallen short.
However, that could all change on Wednesday. A closer look at the two teams reveals a few factors that could tilt the result of the crucial World Cup qualifier in favor of the Americans.
It seems obvious that this U.S. team will be a different one, but it bears repeating because the smackdown it received from Mexico in the Gold Cup final last month is being hailed so regularly as proof of Mexico's return to the top of the CONCACAF mountain.
While both sides left top players out to rest or recover, the disparity in the number of those first-choice performers is very revealing. Bob Bradley called in only three players from that infamous 5-0 loss to the American training camp in Miami: Brian Ching, Chad Marshall, and Stuart Holden. One or more of the trio could also fail to make the final roster for Azteca, as that will need to be trimmed down by two.
Javier Aguirre, meanwhile, brought in 12 players from the Gold Cup final to Mexico's preparatory roster. Given the injury to Barcelona defender RafaelMarquez, Aguirre will drop only one player for his game-day list.
The full dozen of Mexico's Gold Cup players could thus face the U.S. in Azteca, while only one individual (or perhaps none, depending on substitutions) would return the favor.
In other words, the experience Mexico gained against the U.S. players in the Gold Cup doesn't apply to the Americans they will face in Azteca.
The fact that Wednesday's U.S. team will be an almost entirely different side than that of the Gold Cup final does not mean Mexico's win was insignificant. The gaudy goal total certainly captured the attention of all the American players, as did the fervid celebrations of Mexico's players.
Any complacency the U.S. may have felt, given Mexico's current fourth place in qualifying, was obliterated by the Gold Cup. Instead, players are focused on revenge and redemption for the U.S cause.
"I guarantee they're going to be more motivated because of that result," said Gregg Berhalter, a veteran of Azteca bouts in 2001 and 2005.
In the big picture, and especially given Mexico's precarious place in the Hexagonal standings, it may not have been the best idea to give the Americans extra reasons to enter Azteca with fire in their bellies.
At least one interested observer believes El Tri would keep the Gold Cup win in perspective.
"Mexico realizes where that Gold Cup final stands in the rankings of things right now," said Cobi Jones, another player with years of duels against Mexico under his belt. "It wasn't as important, to be honest, as the qualifier."
Psychologically, however, when teams have a rally point to push players for every bit of effort, it can help give them an edge.
The last time the U.S. squad marched into Azteca, back in 2005, Donovan came into the match from Germany, where he'd fallen out of favor at Bayer Leverkusen. He wasn't playing in games and his form was adversely affected as a result.
Donovan still managed to assist on the goal for the Americans that day when he set up Eddie Lewis, but he was missing his usual sharpness and game fitness.
Though many decried his decision to return to MLS, Donovan capitalized on his regular play to lead the league in goals last season. He also helped the U.S. reach the Confederations Cup final this year.
Donovan comes into the Mexico match fully fit and having scored an impressive goal for the Galaxy over the weekend. Like other key U.S. players, it will be his second Azteca appearance, so the intimidation factor of the venue will likely have less of an effect.
If anything, Donovan seems to have embraced his role as the target of ire for Mexican fans. They may have puzzled him in the past with their vehemence, but now he has said he appreciates that they care so much about the game.
It's not easy to play flowing, creative soccer under pressure, and Mexico desperately needs every home win in its qualifying campaign. Even in situations where less was at stake, such as the away game against the U.S. back in February, Mexico's players were jittery, lacking composure in front of the goal. That proved fatal to their cause in that match.
Though the U.S. isn't in first place in qualifying, it is tucked into a comfortable second place. In this context, as the away team, the points against Mexico are not so vital. The fact that Mexico will be pushing hard for the win and the full three points could play right into the hands of the U.S. and its preferred counterattack style.
It perhaps isn't surprising that the Mexican squad that turned around the team's recent streak of futility on U.S. soil was a youthful one. Fresh faces aren't as troubled by the burden of history or the pressure of what is supposed to happen.
This carpe diem mentality served the U.S. well in the Confederations Cup against Egypt and Spain. With nothing really to lose because so many wrote them off early, the Americans came out fearlessly and played well.
Granted, Bradley's reliance on youth was based partly on necessity because Ching was injured. Nonetheless, his faith in giving inexperienced players starts has paid off in a squad that has the vitality of new blood with battle-tested awareness.
Despite all the above factors, Mexico is still favored to win, as the team always is against any opponent in Azteca. However, if the U.S. pulls off the upset, these five key elements will have undoubtedly played a role.