After securing a slot in the Champions League last 16 in mid-week, Manchester United will look to drive home their advantage in the Premier League when they visit Aston Villa this weekend.
United moved to the top of the pile by beating Arsenal 2-1 last weekend and with nearest rivals Chelsea and Manchester City both in action on Sunday, victory at Villa Park would put Alex Ferguson's men four points clear.
Having beaten Chelsea and Arsenal in their last two league outings, United now embark upon a kinder run of fixtures that includes a trip to Norwich City before home games against Queens Park Rangers and West Ham United.
Wednesday's 3-1 win over Braga in Portugal means Ferguson can afford to rest players in United's two remaining Champions League group games, so the domestic title race will now be the number one priority until the end of the year.
Villa are just one place above the relegation zone, and United striker Wayne Rooney says his side should show no mercy as they bid to stretch their lead at the summit.
"There have been games this season where we've been fantastic, and there have been games where we've had to grind out results," he told Sky Sports.
"We're in a good position and we know we can play better football. Now we have a run of games where we feel we can get maximum points, so hopefully we can do that."
Arsenal's Champions League status is less secure, Tuesday's 2-2 draw at Schalke having left them in second place in Group A, and last weekend's loss at Old Trafford saw them fall to seventh in the Premier League.
Arsene Wenger's side have won just two of their last six games in the league and will be without the suspended Jack Wilshere when they host Fulham, who are level on points with Arsenal despite a run of one win in five matches.
Arsenal have seen Everton, Tottenham Hotspur and even West Bromwich Albion steal a march on them in the race for Champions League qualification, and Theo Walcott says his team must now stand up and be counted.
"It is going to be a tough month for us now," said the England winger, who scored his side's opening goal in Gelsenkirchen.
"It is going to test us all, not just physically but mentally as well, and I think we are ready for it."
Everton go into Saturday's visit of Sunderland in fourth place, but they are hoping to end a sequence of four straight draws, having being denied victory at Fulham last weekend by a 90th-minute Steve Sidwell goal.
West Brom, meanwhile, will have their work cut out away at Wigan Athletic, who are bidding for a third consecutive victory after wins over West Ham and Spurs.
It could be a decisive weekend for bottom side Southampton, who host Swansea City amid speculation that coach Nigel Adkins' position is under threat after eight defeats in his side's first 10 matches.
Second-bottom Queens Park Rangers take their bid for a first win of the season to Stoke City, while third-bottom Reading will hope to close the four-point gap between themselves and Villa when they host Norwich City.
Tottenham's trip to Manchester City takes centre stage on Sunday, when the defending champions will seek to bounce back from the 2-2 draw with Ajax on Tuesday that left them hovering above the trapdoor in the Champions League.
Chelsea would have been in a similar position had it not been for Victor Moses' injury-time winner against Shakhtar Donetsk, which will give the European champions a spring in their step ahead of Sunday's visit of Liverpool.
Fixtures (1500GMT unless otherwise stated)
Wigan Athletic v West Bromwich Albion, Southampton v Swansea City, Stoke City v Queens Park Rangers, Reading v Norwich City, Everton v Sunderland, Arsenal v Fulham
Aston Villa v Manchester United, Manchester City v Tottenham Hotspur (1330GMT), Newcastle United v West Ham United, Chelsea v Liverpool (1600GMT)