The game will be the two squads' first meeting since KC beat the Bills 13-10 in an overtime thriller last October.
It will also feature a former offensive coordinator going against his former boss as well.
Bills' second-year head coach Chan Gailey was fired as the Chiefs' OC right before the '09 season began by Todd Haley.
Gailey will get his chance at revenge against his old boss this weekend, after losing to him last year.
This game will also feature one of the most dynamic rushing attacks in the NFL with Kansas City, against what should be an improved Bills' defense.
KC's Jamaal Charles was second in the league in rushing a season ago, and he will be getting help from veteran Thomas Jones, Pro Bowl fullback Le'Ron McClain and speedy playmaker Dexter McCluster in the backfield.
And if the Chiefs are not running the ball, QB Matt Cassel will likely be airing it out to Pro Bowl wideout Dwayne Bowe or new slot receiver Steve Breaston.
Defensively for the Bills, they will try to slow down the Chiefs' potent rushing attack with Pro Bowl defensive tackle Kyle Williams and new ILB Nick Barnett.
Buffalo will also be relying on CBs Leodis McKelvin and Terrence McGee to shut down Cassel and the KC passing attack.
On the offensive side of the ball, the Bills will likely have their work cut out for them in this game.
Harvard-grad Ryan Fitzpatrick will once again be leading the way for the Buffalo offense, with veteran Fred Jackson and second-year man C.J. Spiller spear-heading the ground game.
Sophomore receiver Stevie Johnson will also be someone to look out for when the Bills are passing the ball.
The Chiefs will counter with a young, talented defense that includes the likes of Pro Bowler and last year's AFC sack leader Tamba Hali.
Veteran ILB Derrick Johnson and rookie OLB Justin Houston will join Hali in the linebacking corps, while Pro Bowl safety Eric Berry and polished CBs Brandon Flowers and Brandon Carr help give KC a solid secondary unit.
Key Matchup: Jamaal Charles vs. The Bills Defensive Front Seven
Last season, the Bills were one of the worst teams in the league at giving up yards on the ground. This included the 177 yards that they allowed to Chiefs' star RB Jamaal Charles when the two teams met in Week 8. The Bills cannot let this happen again if they want to keep this game close.
Prediction: Chiefs 24, Bills 10
I see both teams struggling out of the gate, but in the end, the Chiefs just have too much firepower on the offensive and defensive side of the ball for the Bills to overcome.