Monday 10 October 2016 08:48, UK
Minnesota Vikings protect their undefeated record against a J.J Watt-less Houston Texans, while Super Bowl champions Denver Broncos host Atlanta Falcons live on Sky Sports 2 and surprise package Philadelphia Eagles return from their bye week at Detroit Lions.
Odell Beckham Jr and his New York Giants (2-2) are at the Green Bay Packers (2-1) in the late game, live on Sky Sports 2 from 1am.
The spotlight is also on the Cleveland Browns in Week five as Tom Brady returns to a 3-1 New England Patriots positioned to make a run at his seventh Super Bowl appearance.
The superstar quarterback missed the opening four games of the season after ultimately losing his legal battle against suspension for the 2015 "Deflategate" saga.
The timing of the 39-year-old Brady's return therefore could not have been better as the Patriots travel to Cleveland (0-4), the only team in the league yet to win a game.
"It is a lot of fun to be back," Brady said this week after training with his team-mates for the first time this season on Monday. "I haven't had the chance to be out there for four weeks. I've been watching my teammates go out and try to play at their very best, and they performed very well. I'm excited to go out there and join them."
Minnesota face the Texans after their Monday night win over the Giants, live on Sky Sports 2 from 6pm.
Not since 1988 have the Vikings allowed fewer points (50) through four games than this season. They also lead the NFL with a plus-10 turnover margin; their only giveaway was a lost fumble by safety Andrew Sendejo during his own fumble return.
They go to Houston, who have beaten Chicago, Kansas City, and Tennessee in unimpressive fashion, and didn't show up for their toughest opponent, a 27-0 loss at the Patriots. But even without superstar defensive end J.J. Watt, the Texans have been difficult to move the ball against.
The Broncos face a home game against the Falcons (3-1) in an intriguing duel which pits the formidable Denver defense against the in-form visiting offence, live on Sky Sports 2 from 9.05pm.
The Falcons arrive at Mile High brimming with confidence, quarterback Matt Ryan throwing for 503 yards and four touchdowns in a shellacking of the Panthers last weekend.
Atlanta are averaging 354.2 passing yards per game and with 152 points is leading the league with an average 38 points per game.
The Broncos defence, meanwhile, has only given up an average of 169.5 passing yards per game each season, with cornerbacks Aqib Talib and Chris Harris Jr. only conceding six passes of 20-plus yards.
Philadelphia return from a bye week looking to defend their unbeaten start for what should be a straightforward assignment against the Lions, with rookie quarterback Carson Wentz boosted by the return of tight end Zarch Ertz, one of his top receiving weapons.
The Giants head to Lambeau Field with their assistant coach Ben McAdoo, a former Packers assistant coach from 2006-13, now in their ranks.
Clay Matthews, Letroy Guion, Datone Jones and Morgan Burnett all returned to practice on Monday and are in line to make a return for the hosts.
Marquee pass-catcher Odell Beckham Jr managed just three catches for 23 yards in their defeat at Minnesota on Monday and he will hope for an improvement.
Packers cornerback Sam Shields has been ruled out of the game due to the concussion he sustained in the season-opening win over the Jacksonville Jaguars.
