Liverpool can expect a hostile reception when they travel to Newcastle on Monday amid their pursuit of wantaway Magpies striker Alexander Isak, while Manchester City and Tottenham face off in an early examination of their ambitions for the season.
Across Merseyside, a new era begins for Everton on Sunday when they welcome Brighton for the first competitive game at their new 53 000-capacity stadium.
We look at the major talking points ahead of the second weekend of the Premier League season:
ISAK FUTURE HANGS OVER NEWCASTLE, LIVERPOOL
Isak is set to sit out the meeting between his current employers and his preferred destination as a stand-off over the Swede's future rolls into the final week of the transfer window.
Newcastle insist the 25-year-old will not move unless they can source an adequate replacement and Liverpool meet their British transfer record price tag of a reported £150 million ($202 million).
Liverpool have had one bid worth £110 million rejected with their business not yet concluded despite splashing £300 million on new recruits.
Isak broke his silence on Tuesday, saying his relationship with Newcastle "can't continue" after losing trust in the club.
However, the early season form of Hugo Ekitike has tempered the need for Premier League champions Liverpool to meet Newcastle's demands.
The French forward, who rejected Newcastle's advances to join the Reds, registered a goal and an assist on his Premier League debut in Liverpool's rollercoaster 4-2 win over Bournemouth.
The teething problems for Arne Slot's new-look side have been in stopping the flow of counter-attacks against them, but Liverpool should be stronger for the return of midfielder Ryan Gravenberch from suspension at St James' Park.
Newcastle's lack of firepower without Isak was exposed as they failed to break down 10-man Aston Villa in a goalless draw on the opening weekend.
It has been another frustrating week for Eddie Howe in the transfer market as his attempts to land Brentford striker Yoane Wissa have stalled.
SPURS A REMINDER OF MAN CITY DEMONS
City's 4-0 demolition of Wolves on the opening weekend sent a strong message of intent after a season to forget.
The visit of Spurs is a painful reminder of City's fall from grace last season as Tottenham ran riot with a 4-0 victory at the Etihad in November, in the midst of a run of one win in 13 games for Pep Guardiola's men.
Guardiola said his squad has been infused with "fresh energy" after new signings Tijjani Reijnders, Rayan Cherki and Rayan Ait-Nouri impressed at Molineux.
But a tougher test lies in wait against City's bogey team of recent years.
Spurs have lost only one of their last four league visits to the Etihad and scored at least twice on every occasion.
New boss Thomas Frank has already shown his ability to adapt in very nearly masterminding a Uefa Super Cup victory over European champions Paris Saint-Germain before a late collapse.
Tottenham's Premier League campaign also got off to a flier with a 3-0 win over Burnley.
EVERTON'S NEW ERA
Everton's new season got off to a frustrating start in a late 1-0 defeat by Leeds.
But the hope of a bright future is the club's new state-of-the-art home on Liverpool's docklands.
After decades in the doldrums for one of England's historically most successful clubs, Everton are banking on the Hill Dickinson Stadium to help bankroll a change in fortunes.
But the move from Goodison Park, which had been home of the Toffees since 1892, is also fraught with risk.
Goodison's intimidating atmosphere played a big role in helping save Everton from the drop in a series of difficult seasons in recent years.
On the evidence of Monday's defeat, the Blues need their new home to be just as much of a fortress to avoid another relegation scrap.
Friday
West Ham v Chelsea (9pm)
Saturday
Manchester City v Tottenham (1:30pm), Bournemouth v Wolves, Brentford v Aston Villa, Burnley v Sunderland (all 4pm), Arsenal v Leeds (6:30pm)
Sunday
Everton v Brighton, Crystal Palace v Nottingham Forest (both 3pm), Fulham v Manchester United (5:30pm)
Monday
Newcastle v Liverpool (9pm)