Manchester City must prove they can cope without influential midfielder Rodri as the Premier League champions head to Newcastle.
Erik ten Hag will be under pressure to get Manchester United back on track against Tottenham, while Arne Slot has an embarrassment of riches at Liverpool.
AFP Sport looks at three talking points ahead of this weekend's action:
RODRI ABSENCE PUTS MAN CITY TO THE TEST
A pall of gloom descended on the Etihad Stadium when Rodri crumpled to the turf after a collision with Thomas Partey in the first half of Sunday's bruising 2-2 draw with Arsenal.
Rodri has become indispensible to Pep Guardiola's team and that knowledge was at the core of the audible anxiety when the Spain star limped off with knee ligament damage.
The 28-year-old, one of the leading contenders to win this year's prestigious Ballon d'Or award, is expected to be sidelined for several months in a major blow to City's hopes of winning the Premier League title for a fifth successive season.
City have not lost any of the last 48 Premier League games in which Rodri has featured, with their three top-flight defeats last term all coming in his absence.
Now Guardiola must find a way to replace Rodri for the foreseeable future, starting with the league leaders' trip to Newcastle on Saturday.
Guardiola's first option to deputise for the Euro 2024 winner could be Mateo Kovacic, who featured in the role when the Spaniard missed the first four games this season with a hamstring injury.
Ilkay Gundogan and Rico Lewis, a versatile defender who Guardiola has occasionally used in midfield, could also fill in, although Kevin De Bruyne's current thigh injury is a further complication.
"Rodri is not here. A problem? Yes. But complain? Absolutely not," Guardiola said.
"This is the challenge. Let's go with what we have to Newcastle to try to win the game and do what we have done for many years. It is as simple as that."
MAN UNITED MUST FIND KILLER INSTINCT
Erik ten Hag has urged Manchester United to find the cutting edge so badly lacking in their frustrating draws with FC Twente and Crystal Palace.
United failed to convert any of their 15 attempts on goal in the 0-0 stalemate at Palace last weekend, then mustered scored only once from 19 efforts in the 1-1 draw with Twente in their Europa League opener on Wednesday.
With only three wins from seven games in all competitions this season, United have been far from convincing and the pressure on Ten Hag is beginning to mount again.
Saved from the sack only by United's shock FA Cup final win against Manchester City last season, Ten Hag desperately needs a sustained winning run, a task that starts with making them more ruthless in front of goal.
"We have to be more clinical in such situations, but I don't think that was the only problem. It's also a question of mentality," he said prior to Sunday's showdown with Tottenham.
SLOT READY TO ROTATE LIVERPOOL STARS
Arne Slot rarely rotated his best players during his time at Feyenoord, but the Liverpool boss has quickly realised he cannot afford to use the same philosophy in the gruelling Premier League.
Fortunately for Slot, he has a wealth of attacking options at his disposal when he needs to freshen up his team, as he showed during Wednesday's 5-1 rout of West Ham in the League Cup third round.
Slot has two players for every position across the front line, with Diogo Jota and Cody Gakpo scoring twice against West Ham, while Federico Chiesa and Darwin Nunez made their first and second starts this season respectively.
That allowed Mohamed Salah and Luis Diaz to start on the bench and, ahead of Saturday's trip to Wolves, Jota said: "We know the staff work on managing the players and their load. A lot of things are coming and we want to be in the best place possible."
Fixtures
Saturday (1400 GMT unless stated)
Newcastle v Manchester City (1130), Arsenal v Leicester, Brentford v West Ham, Chelsea v Brighton, Everton v Crystal Palace, Nottingham Forest v Fulham, Wolves v Liverpool (1630)
Sunday
Ipswich v Aston Villa (1300), Manchester United v Tottenham (1530)
Monday
Bournemouth v Southampton (1900)