Champions Arsenal will expect to extend their record unbeaten league run to 49 with a home victory over Aston Villa but their chief title rivals face tricky away trips.
Manchester United, who are lagging nine points off the pace in fourth, face a lunchtime kickoff at Birmingham City whose manager, former United defensive stalwart Steve Bruce, will be seeking a big improvement from his team.
United manager Alex Ferguson knows his side have little margin for error if they are to seriously challenge Arsenal and Jose Mourinho's Chelsea and he will have been relieved to see his players return from international duty unscathed.
Wayne Rooney, who like defenders Gary Neville and Rio Ferdinand, featured in England's victories over Wales and Azerbaijan, is expected to start his third game for the club, although Ferguson will be wary of overplaying the 18-year-old.
"The next step is to balance it all," Ferguson said of the forward who scored a stunning hat-trick on his debut against Fenerbahce in the Champions League on his comeback from a broken bone in his foot.
"We've got to remember his age. We want him to be a top player in four or five years' time. That means careful attention like all the young boys at the club."
With Cristiano Ronaldo scoring twice for Portugal in the 7-1 rout of Russia and Ruud van Nistelrooy netting two in the 3-1 Dutch victory over Finland, United should be firing on all cylinders against Birmingham.
Bruce, however, will send out a team containing snarling midfielder Robbie Savage and the former Old Trafford reject will be itching for a battle after the frustration of missing Wales's defeat by England through suspension.
Second-placed Chelsea will be without injured Ivorian striker Didier Drogba for the trip to Manchester City after he underwent minor surgery on his groin.
Drogba has scored four goals for the Londoners this season and Mourinho will be expect the likes of Joe Cole, Eidur Gudjohnsen and Damien Duff to start contributing more to boost Chelsea's unimpressive goals tally of eight.
The Portuguese coach has no such worries at the back, with his John Terry-inspired back four having conceded just one goal in eight league matches.
City will rely heavily on the pace of England's Shaun Wright-Phillips and Frenchman Nicolas Anelka to try and unsettle Chelsea's watertight rearguard.
Arsenal's defence has been porous in comparison to Chelsea's, but a whopping 26 goals at the other end have made Arsene Wenger's Gunners invincible so far.
Thierry Henry scored a memorable backheel in the 4-0 defeat of Charlton Athletic two weeks ago and the Frenchman was on target for his country against Cyprus on Wednesday.
With Dennis Bergkamp rested and Jose Antonio Reyes safely back from international duty with Spain, Arsenal's spoiled fans will be hopeful of another free-flowing demolition job.
Everton, the surprise package in third place, will aim to bounce back from a 1-0 home defeat by Tottenham Hotspur last time out when they host Southampton.
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