The bad news is they travel to a tough place to play to face a one-loss team in the Arizona Cardinals that is surprising people more and more by the week.
Here's a breakdown of some of the key matchups, with some numbers of note along the way.
What's At Stake?
After starting 2-1, the Bills have dropped two straight and are now in a three-way tie at the bottom of the division.
Their defense has been victimized over the past two weeks, giving up 90 points in the span of 86 minutes to the Patriots and the 49ers.
The Cardinals offense, however, is not nearly as loaded as those units. Their offense has scored more than 20 points in just two of the team's five games this season, and just three points this past week against the St. Louis Rams.
After starting out undefeated, the Cardinals have looked vulnerable in their past two games and are in the throes of a heated race for the NFC West.
Key Matchup: Cardinals Defensive Line vs. Bills Offensive Line
It's a clash of titans in the trenches.
With Kraig Urbik, Chad Rinehart and Cordy Glenn all listed as questionable—and presumably out, according to Joe Buscaglia of WGR 550 Sportsradio—the Bills could have a harder time than usual of getting the ball moving on the ground.
For the Bills, it will come down to their ability to run the ball against favorable defensive looks.
The Cardinals have lined up in a 2-4-5 front in 2012, and were able to hold the Patriots to 90 yards rushing and 3.2 yards per carry predominantly from that front, the reason being that they weren't getting quite enough push on the line of scrimmage. If you can't run the ball against that kind of defense, you're going to have trouble.
The Bills will need to be able to run the ball against favorable looks to force the defense to back off a bit.
Biggest Advantage for the Bills
It may sound foolish, but the Cardinals are among the worst offenders of penalties in the league, drawing an average of 6.4 penalties per game and getting penalized for an average of 63 yards per game.
The Bills, on the other hand, are right around the middle of the pack with 5.8 penalties per game, but their penalties only average 37.4 yards per game—that's the third-lowest average in the NFL.
If the Bills can play sound football—not turning the ball over (more on that next) and not getting penalized—they will severely increase their chances of winning.
Biggest Advantage for the Cardinals
Their ability to create turnovers, and the Bills' penchant for giving them up.
The Cardinals rank fifth with 11 turnovers on defense, while the Bills have been the league's fourth-most friendly team to opposing defenses in giving up 13 turnovers of their own.
To say that a team has a better chance of winning the game when they win the turnover battle is like saying I have a better chance of getting fat if I eat a lot of cheeseburgers, but the Cardinals could make easy work of the Bills if they're unable to correct their ball-security issues.
Best Video Tangentially Related to the Game
Great video to preview the game from Football Gameplan on YouTube.
Bills Will Win if...
Their offensive line can give Ryan Fitzpatrick time in the pocket.
The Bills love the short and intermediate passing game, but the Cardinals rank fifth in sack percentage, bringing down opposing quarterbacks on 8.7 percent of drop-backs. They did a great job at keeping Fitzpatrick clean through the first three games and rebounded well after giving up three sacks against the Patriots.
Fitzpatrick has only gone deeper than 15 yards on 19.2 percent of his passes this season, according to Advanced NFL Stats. That ranks 19th in the NFL. That number may seem low, but in the Bills' two wins this season, that number has been lower than 10 percent.
While part of that could be attributed to the running game and the impact that has had on the Bills need for big plays in the air, it's clear that the less Fitzpatrick is asked to carry the offense, the better Buffalo's chances of winning.
Cardinals Will Win if...
They can shut down the Bills' running game.
As alluded above, forcing Fitzpatrick into situations where he must carry the offense is the easiest way to force him into mistakes.
The battle of Buffalo's running game against Arizona's run defense will be a clash of titans, of sorts, with the Bills currently ranking fourth with 5.1 YPA and the Cardinals ranking eighth on defense with just 3.6 YPA allowed on the ground.
The aforementioned injuries will play a huge role in the Bills' ability to move the ball on the Cardinals in the running game, and backups like Sam Young and Chris Hairston could have their hands full with a dominant front seven.
This is as evenly matched as you'll see in a 2-3 team up against a 4-1 team.
That being said, it's hard to predict a win for the Bills when the team can't seem to get out of its own way, especially when the quarterback seems to be at the source of the problems.
The Bills defense has performed well when they get turnovers, but they need to avoid turning the ball over themselves against a Cardinals defense that is good at forcing them.
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.
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