It's a bicoastal and interconference grudge match that pits the best scoring offense from New England (36.3 per game) against the toughest scoring defense from San Francisco (14.2) in what could be a Super Bowl preview.
The Patriots (10-3), who have won seven straight games overall and 20 in December, have been dominating. Four of their last six victories have been by at least 28 points, including Monday night's 42-14 victory over the Texans, who had one loss and are the AFC's top seed.
The 1999 Rams (five) and the '96 Packers (six) - both of whom won the Super Bowl those seasons - are the only other teams since the 1970 merger to win more than four games by 28 points in a season.
"Well, it's a big challenge and a big task to put pressure on Tom Brady when he's so good with every detail of his game," 49ers coach Jim Harbaugh said. "Everything is so refined. There are not a lot of tips you can get or clues even when he's in the shotgun for example. It's a big task and that's something that we would like to get done. And I think we're up for it and like I said, our guys are excited to go play this game."
Outside linebacker Aldon Smith has 19.5 sacks and needs just three to tie Michael Strahan's single-season record.
"A really, really talented defense," said Patriots offensive coordinator Josh McDaniels. "I mean, this is as good as we're going to face. We certainly have a great deal of respect for the way they're coached, the way they way, the style of defense they have. They have great players at all three levels of their defense, Pro-Bowl caliber players.
"This will be a tremendous challenge for us. Really, we're going to have our hands full with just the preparation and getting ourselves ready to play against a really, really special defense."
Should be a special night.
A look at the three keys for each team:
Hold the fort early: During their seven-game winning streak, the Patriots have outscored their opponents by nearly 100 points (163-64) in the first half. They come out with an aggressive gameplan and a quick no-huddle attack with the goal of jumping on the opponent early and taking them out of their offensive gameplan.
That plays right into the hands of the Patriots' defense, which has improved of late but still has some issues in the pass game. The 49ers are a team that likes to stay balanced offensively and let their defense do much of the heavy lifting, which allows second-year quarterback Colin Kaepernick to stay in his comfort zone.
The 49ers have not had a chase many high-powered offenses from behind this season. If they fall behind Tom Brady early, the 49ers might not have the ability to come from behind with an inexperienced quarterback.
Be physical with Welker and Hernandez: With tight end Rob Gronkowski possibly out after forearm surgery, receiver Wes Welker and Aaron Hernandez are carrying the load for the Patriots' offense because they are so difficult to cover one-on-one.
Welker has to be bracketed by a defensive back and linebacker because no cornerback can deal with the option routes that he and Brady work so well.
Watch the play-action: Nobody runs more or better play-action than the Patriots. Conversely, the 49ers' inside linebackers and safeties like to play downhill to stuff the run. The Patriots are going to stay balanced and run their play-action passes, which killed the Texans. If the 49ers bite on the fakes, they're going to be torched as bad as Houston and the score is going to get out of hand.
Stop the run: The 49ers will give standout running back Frank Gore all the touches he can handle to make sure quarterback Colin Kaepernick doesn't have to beat the Patriots by himself. If the Patriots can limit the run, that puts Kaepernick in tough down-and-distance situations on second and third downs, which will make it easier to defend.
Make Kaepernick beat you from the pocket: Expect the Patriots to be very careful with the pressure they apply to Kaepernick because he's a dynamic athlete that can take off from the pocket and score 50-yard touchdowns, which he did last week against the Dolphins. He's also at his best throwing the ball as plays break down.
Protect Brady: The Patriots are going to have a lot to handle on the offensive line between outside linebackers Aldon Smith and Ahmad Brooks, and ends Justin Smith and Ray McDonald. The Smith duo is perhaps the best stunting tandem in the league. They will work together by having Justin Smith take offensive linemen outside, while Aldon Smith crosses behind and rushes from the inside.