Here are five things to keep an eye on as you watch the game on Sunday:
1. Score early
The San Francisco 49ers (2-2) have scored 88 points in their first four games combined, and 72 of those points have come in the first halves of those games.
In three of the four, the 49ers scored a touchdown on their first offensive drive.
Therefore, the Kansas City Chiefs need to be ready on both sides of the ball to contend with a team that likes to make an early impact.
"You always want to get off to a good start," quarterback Alex Smith said. "You always want to get out in front and get into a lead and help your defense. Every week, it's important but probably even more important when you're playing good football teams, and this is a good football team."
The 49ers have been outscored in the second half of their four games by a total of 52 to 16.
Especially because the game is on the road, the Chiefs could really help themselves by getting out to an early lead.
2. Committing to the run
This season, the Chiefs rank eighth in the NFL in highest percentage of running plays called at 47.4 percent. They've committed themselves to running the football, and they've been successful, averaging 145 yards per game on the ground.
Consequently, the 49ers are the No. 2 defense in the NFL against the run, giving up just 69.8 yards per game so far this season. They've only given up six runs of 10 yards or more, which ties them for third-best in the NFL.
The Chiefs racked up more than 200 yards on the ground last Monday night against the Patriots.
Offensive coordinator Doug Pederson knows that keeping Jamaal Charles, Knile Davis and company involved in the ground game, even against a stingy 49ers group, is the key to success on offense.
"I mean they're really good against the run," Pederson said of the 49ers defense. "That's an element that the last couple of weeks, offensively, we've had success running the football and I think as play callers, we continue to call runs."
Pederson acknowledged that while the Chiefs have had success in the run game recently, they're going up against one of the best defensive lineman in the NFL on Sunday in former Missouri Tiger Justin Smith, who has been making plays for over a decade in the trenches.
"He's a great player—a Pro Bowl guy and a smart guy," Pederson said of Smith. "He's going to listen to your calls up front. He's going to listen to what Alex (Smith) is saying. He's going to put calls on with his guys on defense.
"You have to account for him. You have to put four hands on him and you have to somehow slow him down. He's going to get his plays and yet we have to understand where he's aligning and keep four hands on him."
3. Take care of the football
The Chiefs have put up 75 points over the last two games against the Dolphins and Patriots and didn't have a single turnover in their last game Monday.
Taking care of the ball is always important, but on the road against a good defense, combined with the play of the punt coverage unit this season, there's no reason for a forced play that results in a giveaway.
The 49ers defense is already gearing up to try and make you one dimensional by taking away the running game, so eliminating negative plays becomes that much more important.
"It's crucial in any aspect, particularly if your team is trying to take the run game away," Pederson said of eliminating negative plays. "We have to take care of the football, obviously. And then Alex, when we do have a chance to throw the football, he and the receivers have to be on the same page.
"Again, we have to be able to handle crowd noise and all that. So that's a big part of it too."
Back at practice on Wednesday at the University of Kansas Training Facility, Chiefs working on preparation for San Francisco
The 49ers defense ranks third in the NFL in opposing quarterback passer rating against the blitz at just 60.8. They want to shut down the running game and then get after the quarterback on third and long.
Consequently, the 49ers are last in the NFL in third down conversion rate between four and six yards at 71 percent. If the Chiefs can get into third-and-manageable situations, they should have success on offense.
One thing the Chiefs have done a great job of throughout the past couple of games is utilizing different personnel groups to find the advantages they want on a defense. This will help keep them out of bad situations.
Against the Patriots, the Chiefs used eight different personnel groups, and none were used more than 22 percent of the time. They mixed it up well and constantly showed different looks to the defense.
"We're going to continue to roll people, personnel groups, formations, motions," Pederson said of the offense. "It just stresses the defense and puts them on their heels a little bit. But we can sort of dictate to them during the course of the game.
"Our players take pride in that we're going to play a number of guys in those situations and yet I think the biggest thing you're seeing is we're staying healthy at the tight end position, and outside of Donnie (Avery) now, our receivers are healthy and we're able to do that."
4. Stay in rush lanes vs. Colin Kaepernick
Colin Kaepernick is a fantastic athlete, and he's a threat any time he pulls the ball down to take off and run. It will be important for the Chiefs front seven to stay disciplined and contain him in the box.
He's currently the NFL's leading rusher at quarterback with 33 rushes for 187 yards (5.7 ypc).
There are two Chiefs defensive players who know Kaepernick's athleticism very well in linebackers Josh Mauga and James-Michael Johnson, who both played with Kaepernick at the University of Nevada.
"[Kaepernick] is a threat in the passing game and the running game so playing with him for two years, he can run the ball," Mauga said. "If he gets in the opening—nobody's catching him. So if we can keep him away from breaking the strides, I think we'll be OK."
Defensive coordinator Bob Sutton said you can't just sit back against athletic quarterbacks.
"You have to get after those guys and create pressure, but you have to do it with a more disciplined approach," Sutton explained. "Nobody's going to keep him in there all the time."
Staying disciplined and not allowing Kaepernick the ability to get outside and run will be key for the defensive line and linebackers.
5. Plastering receivers throughout entire play
One problem an athletic quarterback can present you with besides running the ball is simply extending the play, which makes it tougher on the defensive backs to stick with their guys.
"The most important thing you do when you play a quarterback that can extend the play is we call it 'plaster,'" Sutton explained. "Whether you're man or zone, once you get to that point, if somebody is in your area, you have to stay on that player.
"The tendency is you want to look back to see what's going on. When you look back, the term that the offense uses is they 'uncover' you. So the quarterback sees you, well, he's going to throw the ball opposite of where you're looking."
One of the guys who will be challenged with this situation is Chiefs cornerback Sean Smith, who respects the ability Kaepernick displays on the field.
"He can scramble and extend the play so you want to stay on your guy," Smith said. "It may look like he's taking off but he'll stop right before the line of scrimmage and chuck that thing across the field."
Smith and the Chiefs defense forced three turnovers from the Patriots and quarterback Tom Brady last Monday in their 41-14 victory. Hopefully the Chiefs defense can slow Kaepernick down enough to pick up their third consecutive win, which would put them above the .500 mark heading into the bye week.