Pep Guardiola's Manchester City travel to Old Trafford for the toughest test of their Premier League title credentials so far, while new Everton boss Sam Allardyce bids to defy Liverpool's "Fab Four" as the northwest derbies take centre stage on Sunday.
City are eight points clear at the top of the table and victory at their fierce rivals could realistically end Jose Mourinho's hopes of landing the club's first league title since Alex Ferguson's trophy-laden reign.
But while Manchester will be at the centre of attention on Sunday, up the road in-form Liverpool host Everton in the season's first Merseyside derby.
Elsewhere, third-placed Chelsea travel to West Ham, Spurs desperately need to end a four-game winless streak in the league and Arsenal will hope to prove that last week's home defeat to United was only a blip.
Here are three big questions ahead of this weekend's Premier League programme:
Will Mourinho attack City?
Jose Mourinho emerged from last week's thrilling encounter at Arsenal with a 3-1 win even though the home side enjoyed 75 percent of possession and had 33 shots compared with United's eight.
United were hailed for producing a counter-attacking masterclass but they were also indebted to goalkeeper David De Gea, who pulled off a string of eye-catching saves.
But how will Mourinho approach the task of slowing City's juggernaut -- made all the tougher due to the suspension of midfielder Paul Pogba, who picked up a red card against Arsenal?
The United boss certainly has the resources at his disposal to trouble City, with an embarrassment of attacking riches including Romelu Lukaku, Anthony Martial, Marcus Rashford and man-of-the-moment Jesse Lingard.
But few expect him to go toe-to-toe with City in a free-flowing game of football, which would be a huge risk against a team that have scored 46 goals in 15 games, with 13 consecutive league wins.
Can Allardyce keep Liverpool's forwards quiet?
Liverpool have put their early-season problems behind them, topping their Champions League group with an avalanche of goals and climbing into the Premier League's top four, with five wins in their past six top-flight games.
After their 4-1 defeat by Tottenham Hotspur in late October, the focus was on the side's porous defence but the 'Fab Four' attackers have since dominated the narrative -- with 46 goals between them this season.
Sadio Mane, Roberto Firmino, Mohamed Salah and Philippe Coutinho have formed a fluid and devastating attacking group but they will come up against arch-pragmatist Allardyce, whose new charges are in the relative comfort of 10th after a tricky spell.
Liverpool manager Jurgen Klopp has pleaded with his free-scoring players not to get carried away after they hammered Spartak Moscow 7-0.
"We should not think it will be like this from now on until the end of our entire lives," he said.
Can Spurs stop the rot?
Tottenham, so long seen as the coming force in English football, suddenly look vulnerable after a disappointing run that has seen them pick up just two points from four outings.
Mauricio Pochettino's side have slipped to sixth in the Premier League table, a whopping 18 points behind leaders Manchester City and they have a fight on their hands to stay in the hunt for a top-four place.
Stoke City are not the scariest of opponents but they travel to Wembley after a morale-boosting win against Swansea City and with the knowledge that Spurs have struggled to put away lower-placed teams at their temporary home this season.
The Argentine was impressed by the performance of his second-string players against APOEL Nicosia in the Champions League.
"To have more players with the confidence to compete for a place is important and will help the team a lot," said the Spurs boss.
"Now we need to be focused on winning in the Premier League again. But this season I think has been a massive step up for us."
Saturday (1500 GMT unless stated):
West Ham v Chelsea (1230), Burnley v Watford, Crystal Palace v Bournemouth, Huddersfield v Brighton, Swansea v West Brom, Tottenham v Stoke, Newcastle v Leicester
Southampton v Arsenal (1200), Liverpool v Everton (1415), Mancheser United v Manchester City (1630)