It's the first of two division matchups between the teams, with both squads coming off vastly different performances in Week 2.
The Arizona Cardinals (2-0) turned in a dominant performance on offense at Chicago, hanging 48 on the scoreboard behind strong play from their offense, defense and special teams.
Meanwhile, the San Francisco 49ers (1-1) seek to rebound from a loss on the road at Pittsburgh, and find an identity on both sides of the ball.
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Here are three keys to the game for both the 49ers and Cardinals.
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1. Force Palmer out of the pocket
The Cardinals' offensive line has done a stellar job of keeping Palmer upright, allowing zero sacks. Because of the protection up front, the signal-caller has had plenty of time to pick apart opposing defenses to the tune of 492 passing yards and seven touchdowns. Get Palmer to move his feet and out of his comfort zone, and the 49ers could find some success on defense in slowing down the Cardinals' aerial attack.
2. Find offensive balance
The 49ers' offense has been a mixed bag. In the season opener, it was the ground game that turned in a big performance; in Week 2, the passing game was on point with the team trailing much of the contest. Torrey Smith alluded to finding success both via the ground and air to keep defenses honest.
3. Control the tempo
A large part of the 49ers success in Week 1 was a result of their ability to run the ball and keep their defense fresh. In Week 2, that was hardly the case. Controlling the clock behind a strong running game from Carlos Hyde would keep Palmer & Co. off the field, which is one way to slow down the Cardinals potent offensive attack.
1. Take some shots downfield
The Steelers found plenty of success attacking the 49ers' secondary, with six plays of 20 or more yards. With the number of weapons at Palmer's disposal, don't be surprised to see Larry Fitzgerald, John Brown and others try to leak behind the defense for big plays.
2. Force Colin Kaepernick out of his comfort zone
The Cardinals are known to bring pressure -- and a lot of it. Kaepernick has yet to turn the ball, but showing different coverages and schemes, and forcing him to make split-second decisions could make the signal caller into a mistake or two.
3. Shut down Carlos Hyde
Though Hyde had a quiet game in Week 2, expect the 49ers to try and run the ball to open up the passing game -- mainly for Kaepernick to try some deep shots down the field for Smith. With the Cardinals known to be aggressive up front and likely to bring pressure, shutting down the run game would make the 49ers offense one-dimensional.