**Top 3 Individual Matchups
1 - Charles Clay vs. Antoine Bethea
**Buffalo's tight end is typically a mismatch against most linebackers and safeties. Bethea is pretty steady in coverage, and the 49ers leading tackler.
2 - Stephon Gilmore vs. Jeremy KerleyKerley is far and away the leading receiver for San Francisco with twice as many receptions as the team's next most frequent passing target. Gilmore figures to be busy on Sunday.
3 - Jerry Hughes vs. Trent BrownBrown is one of the longest-limbed tackles in the league, which could be a problem against Hughes, who can bend the edge and offers an array of pass rush counter moves.
Bills Top 2 Advantages
Good advantage - Pass rushThis task might be a bit harder now with Colin Kaepernick at quarterback for San Francisco, but if Buffalo can hem him in the pocket they could add to their sack total Sunday.
Best advantage - Run gameThe Bills have the third-best rushing attack in football and San Francisco has had tons of problems stopping the run. The 49ers are surrendering almost 150 yards per game on the ground (146.8).
Bills Number 1 Must
Contain KaepernickBuffalo has proven more than capable in stopping the run this season, but a mobile quarterback like Kaepernick is a different assignment altogether. Closing down escape routes for Kaepernick will be critical so he can't take off and create major problems in the open field. Look for Zach Brown to spy Kaepernick on pass plays.
Change at QBBy now everyone is aware that Colin Kaepernick is back in the starting lineup for the 49ers at quarterback. Head coach Chip Kelly benched starter Blaine Gabbert following the team's fourth straight defeat to fall to 1-4 on the season.
Kaepernick is unlikely to add much production to a weak passing game, but does present a more diverse skill set when it comes to running with the ball. Though Gabbert wasn't shy about taking off with the football himself, he doesn't offer the same breakaway speed that Kaepernick does.
Dropping the ballThe 49ers pass game has been anemic through the first five games this season. San Francisco ranks 31st in the league in passing ahead of only the Bills (32nd). One of the issues plaguing the Niners pass game is dropped passes. San Fran has an 8.4 drop percentage, which is close to double the league average. Only two NFL clubs have dropped passes more often than the 49ers this season.
No hankiesIf there is one thing that the 49ers do well it's avoiding penalties. Through the first five weeks this season they've been flagged and assessed just 21 penalties. It's the fewest number of penalties for any team in 2016. An impressive figure when you consider their offense and defense has been on the field for 666 plays.
Run overWhile the 49ers are a respectable eighth in the league in rushing, they've had a lot of trouble stopping any opposing rushers. In fact in their last four games they've allowed their opponent's feature running back to top 100 rushing yards. In Week 2 Carolina's Fozzy Whittaker had an even 100. In Week 3 Seattle's Christine Michael has 106 yards and a pair of TDs. In Week 4, Ezekiel Elliott rolled up 138 yards and a score and last week Arizona's David Johnson had a season-high 157 yards and two scores.
Their task became all the more difficult after they lost ILB NaVorro Bowman to a season ending Achilles injury.
Wait a minuteThe struggles for San Francisco have even stretched into the final two minutes of the half or game. Their offense has yet to score any points in a two minute drill situation. That puts them in a tie for least productive two minutes offense in the league.
Conversely, their defense finds stopping teams in the final two minutes of a half or the game equally as difficult. Through the first five games, the 49ers defense has surrendered 17 points during two minute drills. That ranks last in the NFL.
Red zone groanAlthough the 49ers rank in the middle of the pack when it comes to keeping opponents out of the end zone after they crack the San Francisco 20-yard line (17th) they still give up too much ground. Opponents gain better than four yards per play against the 49ers in the red zone (4.05). That ranks a disappointing 30th in the NFL. In fact more than 57 percent of the time opponents have a successful play in the Niners red area.
Quote of the week
"I would say he's definitely playing with an extra burst. You could tell last year that the hamstring would bother him on certain runs. He couldn't get back to some of the holes he was trying to get to and I think this year he's definitely seeing them and getting back to them with his feet as well." **--QB Tyrod Taylor on LeSean McCoy
Stat of the weekThe Bills are averaging 178.3 rushing yards per game on their current three-game winning streak.
Milestones in reachZach Brown (57) needs 10 tackles to set a franchise record for most tackles in the first games of a season (Kiko Alonso, 66 - 2013).
Dan Carpenter needs three field goals to reach 100 as a Bill.
Stephon Gilmore needs three tackles to reach 200 in his career.
Final noteThe Bills have won their last three games against NFC opponents.