Manchester City's defensive resilience and offensive brilliance so far this season face arguably their sternest tests on Saturday against champions Chelsea, with the Premier League leaders without full-back Benjamin Mendy and star striker Sergio Aguero.
France full-back Mendy looks set to miss most, if not all, of the rest of the season after undergoing an operation on a ruptured anterior cruciate ligament.
City medical staff say Aguero will be absent for between two to four weeks with a broken rib suffered when a taxi the Argentinian star was travelling in - after attending a concert on his day off - crashed in Amsterdam on Thursday.
City will feel both their absences keenly.
Mendy has been in fine form for City since his £50 million (Dh246m) pre-season move from Monaco, whilst Aguero has scored six Premier League goals this term.
"It's a broken rib. Hurts, but I'm fine, fully focused on recovery," Aguero tweeted after being seen by City medical staff on Friday.
Both City and Chelsea, three points behind both Pep Guardiola's men and second-placed Manchester United, go into Saturday's game on the back of Uefa midweek Champions League victories over Shakhtar Donetsk and Atletico Madrid respectively.
Premier League predictions: Manchester City to earn a point at Chelsea
Champions Chelsea face leaders City in what is likely to be a feisty game
Chelsea manager Antonio Conte is unhappy that, while City played at home on Tuesday, his side have a short turnaround after arriving back in London in the early hours of Thursday morning following their success in the Spanish capital.
"I think we are a bit penalised," Conte said. "Man City is a really strong team. They are scoring a lot of goals [21 in six Premier League games alone], they are in a good moment of form and we have to prepare well [for] this game because it is very important.
"There is the international break [after this weekend]," the Italian added. "My surprise is for this because there is the time [to play the game later]."
United will be huge favourites to beat basement club Crystal Palace at Old Trafford on Saturday.
However Jose Mourinho, like Conte, is not happy with the quick turnaround after United returned from Russia in the early hours of Thursday having beaten CSKA Moscow in the Champions League.
"We have to play against everybody home and away and when I look at the fixtures I only look to the period of time we have to recover from match to match," Mourinho said.
"That's the only thing that concerns me and makes me think. The opposition is not the problem."
Palace have lost all six of their league matches so far this season and have still to score their first top-flight goal of a campaign where they have already dismissed Frank de Boer and brought in former England boss Roy Hodgson - a boyhood Palace fan - in a bid to arrest their slump.
Tottenham Hotspur, fresh from seeing England striker Harry Kane score a hat-trick in a 3-0 Champions League win away to APOEL Nicosia, are at surprise high-flyers Huddersfield Town, while Watford will look to consolidate their position in the top half at West Bromwich Albion.
Elsewhere West Ham United, with just Bournemouth and Palace below them in the table, will hope to ease the pressure on manager Slaven Bilic when they welcome Swansea City to the London Stadium.
The pick of Sunday's three Premier League matches sees Newcastle United manager Rafa Benitez up against former club Liverpool at St James' Park in a fixture long known for producing high-scoring encounters.