The NFL heads south of the border for the first game to be held in Mexico City since 2019 when the San Francisco 49ers take on the Arizona Cardinals on Monday night.
The 4-6 Cardinals could be down to their third-string QB for this one with Kyler Murray still dealing with a hamstring issue and Colt McCoy, his backup in last week's 27-17 win over the Los Angeles Rams, limited in practice over recent days because of an injured knee.
Last week, the Niners improved their record to 5-4 with a 22-16 victory over the Los Angeles Chargers to move within one win of the NFC West-leading Seattle Seahawks.
Kyle Shanahan has been meticulous in his preparation for the clash at altitude and will hope that his premier rushing duo of Christian McCaffrey and Elijah Mitchell can pound the Cardinals' 30th-ranked scoring defense into submission.
What: San Francisco 49ers @ Arizona Cardinals
Where: Estadio Azteca, Mexico City, Mexico
When: 8:15 p.m. ET/5:15 pm PT Monday, November 21st
How to watch: ESPN & stream via fuboTV
Odds: SF 49ers -380, ARZ Cardinals +300
The Cards' defense actually stacks up better against the run than the pass, but San Francisco's rushing attack has been fearsome in recent years.
It feels like Shanahan has another two-headed monster at his disposal again after the return of Mitchell, who came back from a seven-game absence to deliver 89 of the team's 157 rushing yards against the Chargers.
In every one of their four victories this season, the Cardinals held their opponents to under 100 rushing yards and less than 4.0 yards per attempt.
And that mark appears to be something of a barometer for their overall success as Arizona's defense has given up 100 rushing yards or more and an average of 4.2 yards per carry or higher in each of their six defeats.
The Cardinals' quarterback situation is awkward as McCoy, who completed 26 of his 37 pass attempts for 238 yards and a touchdown last weekend, looked good in relief.
He enjoyed success in one of his three previous starts when leading the Cardinals to a 31-17 win at San Francisco last November with an efficient 22-of-26 passing performance for 249 yards.
But McCoy has been limited in practice and if he is unable to go then Trace McSorley, a journeyman with ten pass attempts as a pro who was signed off the Baltimore Ravens practice squad, will see significant action.
That will clearly inhibit Arizona's play-calling ability and determine a more run-centric focus to their overall gameplan.
However, the Cardinals have major injury issues on the offensive line too with at least three starters out, while any hope that left tackle D.J. Humphries could return from a back problem was extinguished by head coach Kliff Kingsbury at his Friday press call.
The 49ers will be worried about DeAndre Hopkins running amok in their secondary and will probably try to double cover him whenever possible - effectively telling Arizona they will have to get other playmakers involved.
But they don't have any with quite the same game-breaking ability as Hopkins, especially with Kyler Murray still not fully fit, although second-year wideout Rondale Moore had a big day when catching nine passes for 94 yards against the Rams last week.
The Cardinals have a below-average rushing attack and one that San Francisco's No.1-ranked run defense should not be manhandled by.
So the Cardinals' offensive hopes will rest on whether they get a level of competency from their quarterback, be it McSorley or a limited version of McCoy.
Arizona's middle-ranking defense will struggle to slow down a supremely talented Niners offense that boasts playmakers like George Kittle, Deebo Samuel, Brandon Aiyuk, and McCaffrey.
It's really hard to envisage the Cardinals being able to hang with San Francisco for long in this Mexican matchup, and if the Niners are the playoff-contending team most believe them to be, they will come back to the US with the win.
The Niners spent the week practicing in Colorado to get used to the high altitude in Mexico City, where the stadium stands at an elevation of over 7,000 feet, while Arizona stayed at home in Tempe.
That could be a mistake that comes back to bite them in the second half of a game that the Niners - who have allowed no points after half-time in either of their past two games - will want to turn into a physical test.
San Francisco ought to cover the -8.5 point Spread, available at -110, without too much trouble.