Liverpool tackle Chelsea as a resurgent City play stuttering champions United in the Manchester derby on a crunch weekend of fixtures in the English Premier League.
In the first "big four" clash of the new season, Rafael Benitez's Reds host Jose Mourinho's Blues in an early test of each side's title-winning potential.
And Manchester United head to Eastlands without last season's top two scorers: the injured Wayne Rooney, and Cristiano Ronaldo, who is suspended.
Manchester City, revitalized under former England boss Sven-Goran Eriksson, have the chance to prove their impressive start to the season makes them serious contenders this season.
The Manchester derby, Liverpool's clash with Chelsea and Arsenal's trip to Blackburn take place tomorrow.
In today's matches, league leaders Everton look to keep up their perfect start at Reading.
Big-spending Tottenham, desperate for a first win, host newly-promoted Derby County and West Ham travel to Birmingham with new signing Kieron Dyer set to make his Hammers debut.
At the Madejski Stadium, two of the toughest teams to break down in the Premier League go head to head.
Early pace-setters Everton have got the better of Tottenham and Wigan so far, but they travel to Reading, whose man-marking tactics squeezed a goalless draw out of Manchester United and gave Chelsea a fright before the Blues ground out a win.
"We'll be playing three from the top six inside a week, and it's as if it's the hardest possible hurdle we could have been set," Royals boss Steve Coppell said.
Everton's new midfielder Phil Jagielka reckons the Toffees are playing so well he faces an extended spell on the bench.
"I can't see the gaffer changing it for Reading," the England B international said. "Nine or even seven points [from the first three games] would be a fantastic start."
Tottenham were tipped to be among the top sides this season but they have lost both their matches so far.
"Now there is more pressure to get a result," said Spurs boss Martin Jol's assistant Chris Hughton.
"I'm sure Derby will try to make it difficult for us but it has to be about us and about bouncing back from two defeats," he said. "It has been a disappointing start for all of us here and we're determined to get back to winning ways."
Birmingham have been frustrated in their matches so far, losing 3-2 at Chelsea and succumbing to a disputed last-minute equalizer in a 2-2 draw at home to Sunderland.
They host West Ham -- who were embarrassed as visitors Manchester City tore them apart in a 2-0 opening day win.
England midfielder Dyer said he was ready to be thrown in to the Hammers team.
"It is probably one of my strengths -- my ability to hit the ground running, so even though I have had a bit of a stop start pre-season if the manager asks me to play at Birmingham on Saturday I would be totally up for the challenge," he said.
Newcastle boss Sam Allardyce takes charge of his first league match at St James's Park as the Magpies host Aston Villa.
England striker Michael Owen could make a welcome return for Newcastle, who have not scored at home since February.
However, Villa boss Martin O'Neill wants his defenders to close down the likes of Owen more.
"If we could just tighten up a little bit, especially when we haven't got the ball, then I honestly believe we will start to do better," the Northern Irishman said. "Once we get going, we'll be fine."