An under-strength Arsenal face a huge test of their Premier League title credentials at rivals Tottenham, while Manchester United boss Erik ten Hag desperately needs a response from his side at Southampton.
AFP Sports looks at the pick of the action as the English top-flight returns from an international break this weekend:
Arsenal have already blinked first in the title race to fall two points behind Manchester City and Liverpool.
The Gunners were held 1-1 at home by Brighton last time out after Declan Rice was harshly sent-off early in the second half.
Rice is therefore suspended for Sunday's north London derby to compound injury woes for Mikel Arteta.
Captain Martin Odegaard is expected to miss three weeks due to an ankle injury picked up on international duty with Norway.
New signing Mikel Merino is also absent from the Arsenal midfield with a shoulder injury.
However, there was some good news for Arsenal as Arteta signed a new three-year deal on Thursday.
"Together with the players and everyone at the club, we are looking forward to the coming years, with our supporters, who have emotionally transformed the club and the team," said the Spaniard.
Arteta has led Arsenal to second-place finishes in each of the past two seasons but he must come up with a masterplan to avoid leaving his side with an early mountain to climb in the title race.
A trip to the Tottenham Hotspur stadium kicks off a daunting run of three tough away games in eight days.
Arsenal face Europa League winners Atalanta on Thursday in the Champions League before a showdown against City.
Just three games into the new Premier League season, Erik ten Hag is under pressure once more after consecutive defeats for Manchester United.
A 3-0 humbling at the hands of Liverpool on the back of a 2-1 loss at Brighton has done little to suggest the Red Devils have made substantial progress from finishing eighth last season.
"We will see where we are in May. It is very early in the season and it is about winning trophies (and) being as high as possible in the league," Ten Hag said on Thursday.
"It (noise around the club) doesn't impact me - I know in the process where we are. We have to integrate a lot of young players in the team."
United head to promoted Southampton on Saturday lunchtime looking to avoid suffering three successive league defeats for the first time since December 2015.
The Saints are yet to register a point from their opening three games after bouncing back into the top flight.
Erling Haaland has started the season in ominous form for anyone hoping to snatch away City's crown after a record four consecutive titles for Pep Guardiola's men.
The Norwegian has scored back-to-back hat-tricks against Ipswich and West Ham, after also netting in the opening weekend win at Chelsea.
Haaland now has eight hat-tricks in just 69 Premier League games and is one of six players to score a hat-trick in two consecutive games.
No one has ever done three in a row, though, and the visit of Brentford to the Etihad offers the prolific 24-year-old a shot at more goalscoring history.
Fixtures (all times GMT)
Saturday
Southampton v Man Utd (1130), Brighton v Ipswich, Crystal Palace v Leicester, Fulham v West Ham, Liverpool v Nottingham Forest, Man City v Brentford (all 1400), Aston Villa v Everton (1630), Bournemouth v Chelsea (1900)
Sunday
Tottenham v Arsenal (1300), Wolves v Newcastle (1530)
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