Here's what to watch for:
All eyes on Tuel: At the start of the preseason, rookie EJ Manuel was the focus at quarterback. Two weeks later, attention turned to Kevin Kolb. And now, with both Manuel and Kolb out with injuries, it's Jeff Tuel's chance in the spotlight. The undrafted rookie has been named the opening-day starter in the event Manuel is not ready to return from a minor procedure on his left knee. Tuel will face more national scrutiny on Thursday night than arguably any other player across the NFL. It's unlikely pressure for a preseason finale, and it will be worth monitoring how Tuel handles being thrust onto the main stage.
How much time for starters? Normally, this is a game that starters either play minimally or sit out entirely. Does the Tuel situation change that? Beyond running back C.J. Spiller, who will not return to the team until this weekend after an excused absence, do the Bills dress their other top offensive players to get them in a rhythm with Tuel? The best guess from this perspective: Yes. The odds are against Manuel being able to return for Week 1, and if you're the Bills, opening against the New England Patriots, you want to make Tuel as comfortable as possible.
Can the defense bounce back? After an encouraging outing against the Minnesota Vikings, the Bills defense laid an egg against the Washington Redskins last Saturday. The run defense was particularly suspect, allowing 208 yards on 43 carries. It's worth noting that the Bills' offensive struggles allowed the Redskins to control the time of possession in that game, but it was hardly a positive performance by Mike Pettine's unit. Even if starters play minimally, getting back on track will be important.
Can corners lock it down? The Bills defense took a big blow on Monday when coach Doug Marrone announced that cornerback Stephon Gilmore would miss 6-to-8 weeks with a fractured wrist. Expect Crezdon Butler to start in his place on Thursday night. He'll be a player worth following during the game. If he struggles, the Bills will be scrambling for another option in their secondary.
Injuries, injuries, go away: After emerging from the preseason opener in Indianapolis with no significant injuries, Marrone probably should have knocked on wood. His squad's health took some major blows over the next two weeks, with Manuel, Kolb, and Gilmore all going down. Another hit to either side of the ball would be crushing heading into the opener. And of course, the Bills probably don't even want to think about what they would do if Tuel was injured Thursday.