Now missing their top two rushers, the Cardinals look to rebound from their first loss of the season while trying to hand the reeling Bills a third consecutive defeat Sunday.
Arizona (4-1) was off to its best start in 38 years before being roughed up in a 17-3 loss at St. Louis last Thursday. Kevin Kolb was sacked nine times, second-year running back Ryan Williams suffered a season-ending shoulder injury and the Cardinals failed to total 300 yards for the fifth time in as many games.
A team which recently believed it was in for a special season now has some serious offensive concerns.
"We'll look at a lot of things that we've got to do, but I'm not going to panic," said coach Ken Whisenhunt, whose team has allowed 17 sacks in the past two games and a league-high 23 overall.
"We've got a team that's tough mentally. They'll bounce back from this."
Though the Cardinals must find a way to better protect Kolb and will use a committee at running back, they could benefit from facing a Buffalo team that has been outscored 97-31 over the last two weeks.
The Bills (2-3) have allowed 1,201 total yards in losses to New England and San Francisco, the most in a two-game span since the New York Yanks (1,227) in 1950. Buffalo surrendered a franchise-worst 621 yards in last Sunday's 45-3 loss to the 49ers, becoming the first team in NFL history to allow 300 yards passing and 300 rushing in the same game.
"We have to figure out what in the world is going on from the first guy to No. 11 on defense," said defensive end Mario Williams, who has managed 1 1/2 sacks after signing a six-year, $100 million contract to leave Houston.
Making matters worse, defensive end Mark Anderson will have surgery on his left knee and will be out indefinitely. Anderson suffered the injury and had difficulty putting any weight on it in the second half last Sunday.
That leaves 10-year veteran Chris Kelsay to take over the starting duties at right end.
While the Bills have the AFC's lowest-ranked defense, surrendering 449.4 yards per game, the Cardinals have the NFC's lowest-ranked offense (273.2).
Arizona's offensive line must improve in pass protection and in run blocking, especially with the top two running backs out of the picture.
The Cardinals rushing attack ranks 31st with 63.4 yards per game, and is without Beanie Wells until late November and Williams once again after he missed last season with a torn patella tendon.
Though the team may look elsewhere for help, LaRod Stephens-Howling, William Powell and Alfonso Smith are expected to share the rushing duties despite combining for 10 yards on 15 carries this season.
"I feel good about the guys that we've got," Whisenhunt said. "We're always going to look to get better at every position. If that opportunity is there, then we'll certainly try to act on it."
Arizona has run the ball just 32 times over the past two weeks while Kolb has attempted 98 passes, throwing for 613 yards. Larry Fitzgerald has caught 25 passes for 270 yards with two TDs in the last three games after catching five for 67 without a score in the first two.
He had two touchdown receptions when these teams last met as Arizona snapped a four-game skid against Buffalo with a 41-17 home win Oct. 5, 2008.
Fitzgerald could be in for another big performance against the Bills, who have allowed four 100-yard receivers in the last two games. Buffalo ranks 31st in scoring defense (35.2 points per game), and nine of its 10 sacks have come in victories over Kansas City and Cleveland.
"We're all to blame," general manager Buddy Nix said. "Let's do better. Hell, let's get it going."
Electing to stay out west and prepare for this contest, the Bills hope the lack of travel will benefit the defense as well as an offense which was held to 204 total yards by the 49ers.
"I think this is a perfect week to get things fixed," center Eric Wood told the team's official website. "We've got an isolated setting. We don't have a whole lot of distractions out here and it's time to get it straight."
With starting offensive linemen Cordy Glenn and Kraig Urbik likely out with ankle injuries, Buffalo's task won't be easy against an Arizona defense allowing 15.6 points per game to rank fifth in the NFL.
Ryan Fitzpatrick threw for 126 yards with an interception while Fred Jackson and C.J. Spiller combined for 53 yards on 16 carries last Sunday. Fitzpatrick has thrown 12 touchdown passes, but five of his eight interceptions have come over the last two weeks.
"We have the talent," Fitzpatrick said. "That's something we know we have."