Where: University of Phoenix Stadium, Glendale, Ariz. (grass, indoors)
When: Sunday, 4:05 p.m., ET (CBS)
Spread: Cardinals by 4.5
Records: Bills (Overall: 2-3, AFC East: 0-2); Cardinals (Overall: 4-1, NFC West: 1-1)
Past results: Two most recent meetings -- Oct. 5, 2008: Cardinals 41, Bills 17; Oct. 31, 2004: Bills 38, Cardinals 14. Series record: Cardinals lead 5-4.
What matters: Can the Bills stop the bleeding on defense? Buffalo’s revamped unit has been torched in back-to-back blowout losses to New England and San Francisco. With the Cardinals up next, the task isn’t as daunting. Arizona has scratched and clawed its way to a 4-1 start, but its offense isn't on the same level as the Patriots or 49ers. The Bills need to show better gap responsibility on defense and avoid missed tackles, which has been a major problem the last few weeks.
Who matters: QB Ryan Fitzpatrick, DE Mario Williams, LB Kelvin Sheppard. Fitzpatrick has been erratic in recent weeks and threw for only 126 yards against the 49ers. He needs to get back to doing what he does best -- read the defense quickly and make the correct decision. He’s struggled with his accuracy and decision-making all season. Williams has been the scapegoat on defense, but it’s not all him. Sure, the Bills expect and need more from their $100 million man (11 tackles, 1.5 sacks), but Buffalo’s entire defense is to blame for the record-breaking losses the past two weeks. Sheppard is another defender who needs to take a step forward. As the MLB in Dave Wannstedt’s 4-3 scheme, he’s expected to be the playmaker in the heart of the defense. So far, he’s been average at best (17 tackles, one sack).
Key matchups: Buffalo’s DL vs. Arizona’s OL, Bills WR Steve Johnson vs. Cardinals CB Patrick Peterson, Cardinals WR Larry Fitzgerald vs. Bills CB Stephon Gilmore. A matchup against the Cardinals may be just what the Bills need to get their defensive line on track. Arizona allowed nine sacks in a Week 5 loss to St. Louis, and QB Kevin Kolb was under constant pressure. Johnson, Buffalo’s top WR, has been more outspoken this week and is fed up with the blowout losses. It will be interesting to see if he plays with more confidence as a result. Fitzgerald is a test for any defense but even more so for Buffalo’s young secondary. The Bills have struggled at CB, and Gilmore -- Buffalo’s first-round pick -- has looked every bit a rookie.
Injuries of note: DE Mark Anderson (knee) is out indefinitely. LT Cordy Glenn (ankle) and RG Kraig Urbik (ankle) are out, but top interior reserve Chad Rinehart (calf) is hoping to return. DT Kyle Williams (ankle) was rested during the week but should be good to go. The Cardinals are without their top RBs -- Beanie Wells and Ryan Williams -- which is good news for Buffalo’s ailing run defense.
Inside stuff: The Bills have spent the week in Phoenix instead of flying to Buffalo following their game against the 49ers. Will the move pay off? Usually, it’s West Coast teams that benefit the most from spending the week in a different time zone, but the Bills are hoping it can help them this time.
Connections: Former Bills QB Frank Reich -- known for bringing the Bills back against the Houston Oilers in the greatest comeback in NFL history -- is Arizona’s WRs coach. He spent 10 years with the Bills as a QB. Bills offensive coordinator Curtis Modkins spent the 2009 season as Arizona’s RBs coach.
Stat you should know: After allowing a franchise-record 621 yards to the 49ers and 580 to the Patriots, the 2012 Bills became the first team in franchise history to allow 500-plus yards in back-to-back weeks.
Record watch: A Fitzpatrick TD to Johnson would make them the fifth tandem in team history to connect on 21 or more TDs.
Looking ahead: The Bills get a bit of a breather in Week 7 following their difficult trip with a home game against the 2-4 Tennessee Titans, although that doesn’t look like a gimme after Tennessee’s win over Pittsburgh on Thursday night. If the Bills find a way to get past the Cardinals, it’s possible that they’ll be 4-3 at the bye, which is remarkable considering how bad the past two weeks have been. The Cardinals could use a win with a brutal three-game stretch around the corner. Following the Bills, the Cardinals have road games at Minnesota and Green Bay and a home game against San Francisco in between.
Prediction: Cardinals 21, Bills 13
For more updates on the Bills, follow correspondent Mark Ludwiczak on Twitter @CBSBills and @MarkLud12.