On the flip side, the Patriots have gotten off to an unexpected 1-2 start and after a tough loss last week against the Baltimore Ravens, New England will have a major chip on its shoulder coming into this game.
But the Patriots have proven to be beatable over the first three games of the season and the Bills certainly have the tools to do it.
Let's take a look at the keys to victory for Buffalo.
Throw the Ball
Ryan Fitzpatrick has done his best to establish the Bills' passing attack, but Buffalo's signal-caller has only broken 200 yards once when he threw for 208 last week against the Cleveland Browns. Overall, the Bills' passing attack is ranked 26th in the league.
Luckily for the Bills, the Pats are not good against the pass. New England comes into this Week 4 matchup ranked 24th in the NFL and are looking to bounce back after Joe Flacco bombed the Pats for 382 yards and three scores in Week 3.
Against the faceless secondary of the Pats, receivers like Steve Johnson and Donald Jones should have ample space to make plays for their quarterback. Look for Buffalo to try and establish the run in order to open up the field for its passing attack to take over the game.
Stop the Run
As long as Tom Brady is behind center for New England, the Pats will always look to throw the ball and most likely, they will be successful doing it. With that being said, there's little any team can do to stop it.
So if the Bills want any hope of slowing down Brady and the Patriots' offense, it will start with stopping the run.
Buffalo can't allow Stevan Ridley and the Pats' 12th-ranked rushing attack to get going, otherwise it could be a long day. If the Bills can stop the run, it will be one less thing they need to worry about and that will turn the Pats into a one-trick pony.
Buffalo would then be able to look for the pass on an every down basis, making it much easier to stop the Patriots' offense and force some turnovers in the process.
C.J. Spiller and Fred Jackson
After the emergence of C.J. Spiller, the Bills now find themselves with two solid backs when combined with Fred Jackson. However, both are listed as questionable for this week with a shot to play on Sunday.
Beyond Spiller and Jackson, the Bills have Tashard Choice who can be a nice backup in this league, but he doesn't offer anywhere near the same skill set as Spiller and Jackson.
It's already a no-brainer that the Bills need their two best backs on the field. Furthermore, Jackson's and Spiller's success on the field will help open up the Bills' passing attack, which will aid in exploiting the weakest part of the Pats' defense.
While Gronkowski is listed as questionable for Sunday, the Pats' tight end is expected to take the field.
But there's no telling what New England will get from its star tight end as Gronk battles a hip injury that could very well slow him down.
With Aaron Hernandez out and Gronkowski battling this injury, Brady could face the prospect of not having two of his favorite targets to throw to and that clearly makes it easier for Buffalo's defense.