The way they responded to their loss to the Minnesota Vikings—by pantsing the New York Jets 34-0 in their own house—it's fair to wonder whether the 49ers will lose another game.
The fact remains, though, that there have been some cracks exposed in the armor.
Here's a game plan for how the Bills could pull off a huge upset against the 49ers.
Shut Down Frank Gore
Fairly basic, but absolutely necessary.
The running game is at the forefront of everything for the 49ers, and that has opened things up for quarterback Alex Smith to have one of the most efficient seasons of his career to date. The Bills will have to win the battles in the trench to slow down the 49ers running game and put the ball in Alex Smith's hands more.
The 49ers will likely try to avoid that happening by continually running the ball, wearing down the defensive line and forcing them to anticipate the run, which will open up the play-action passing game and slow down the pass rush.
The 49ers have been beat by interior-line stunts this year, but those don't work as well when the running game is going strong, as it can leave holes in the line that allow a back to easily penetrate to the second level of the defense. The Bills will have to maintain gap discipline to avoid being exposed for long gains on the ground.
Basically, they'll have to avoid everything that led to the Jets giving up 245 yards of offense on the ground. For instance, on this play, every single Jets defensive lineman gets blown off the ball.
It's not as though the Jets were unprepared—the "I" formation is as clear an indication in today's NFL that the opponent is going to run.
In fact, the Jets were quite ready for the run, with four linemen and a linebacker on the line of scrimmage.
By the time running back Frank Gore takes the handoff, there's plenty of daylight for him to bust up the middle of the defense and pick up 11 yards.
Namely, defensive tackles Kyle Williams and Marcell Dareus are really going to have to win their matchups in the A-gaps if the Bills are going to have any hope of shutting down Gore.
It's up to the defensive tackles to turn in a big performance against a rush attack that's been among the league's best.
Short Stuff in the Air
The 49ers run defense is among the best in the league, giving up 3.2 yards a pop to opposing ball-carriers. The Bills have a top-notch running game, but it wouldn't be surprising to see them struggle a bit. In any event, they won't be able to count on it as much as they have in past weeks.
The Vikings continued to run the ball even when it wasn't effective, and because they were able to stay physical, they wore down the 49ers defense. The Bills may try a similar approach, but as Christian Ponder proved in his big win over the 49ers, they'll have to get something done through the air.
It doesn't have to be spectacular, but it does have to be effective.
Thus far, there have been mixed results from quarterback Ryan Fitzpatrick, who has a completion percentage of 57.6 (ranks 24th in the NFL) and a passer rating of 89.8 (ranks 16th). This season, his passer rating has been as high as 120.1 and as low as 66.5.
His success has been spotty, but one way the Bills have been most successful through the air is with short and intermediate passes; in the Bills' two wins, Fitzpatrick threw just 5.3 percent (vs. Browns) and 8.6 percent of his passes deeper than 15 yards (according to Advanced NFL Stats).
With Carlos Rogers likely blanketing Stevie Johnson for much of the game, the Bills will be trying to win their matchups in the slots over the middle of the field.
They did so against the Patriots early in the third quarter on a play that helped them take a 21-7 lead (I'll let you fill in the blank on how it ended).
The Bills run slants a lot, because it gives Fitzpatrick a big window where he can easily throw the ball in a spot that only his receiver can catch.
Of course, there's a huge window on this play, and Fitzpatrick pulls the trigger to Donald Jones for the easy completion.
What neither he, nor Jones, nor head coach Bill Belichick were anticipating was that safety Patrick Chung would take the world's worst angle, allowing Jones to sneak through the back end of the secondary and scamper 68 yards for a touchdown.
This is just one big-play example of the Bills' effectiveness in the short passing game, and it's not likely that the Bills will hit many big-gainers like this against a 49ers defense that has allowed just eight pass plays allowed over 20 yards, the second-fewest in the league.
That being said, the Bills have done much of their work in the short and intermediate parts of the field, and if the 49ers choose to blitz Fitzpatrick, there could be opportunities on slant patterns for Donald Jones and the like. They need to make things as easy for Fitzpatrick as possible.
The best way to make that work, though, is to hit a big play early. That will force San Francisco to respect the big play and take their defensive backs away from the line of scrimmage, which is where the Bills will be doing a lot of their work with screens and slants.
Erik Frenz is the AFC East lead blogger for Bleacher Report. Be sure to follow Erik on Twitter and "like" the AFC East blog on Facebook to keep up with all the updates. Unless specified otherwise, all quotes are obtained firsthand.