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By the time Arsenal and United kick-off at the Emirates Stadium, Chelsea, who have a game in hand on both teams, could have opened up a four-point lead at the top with a win over Burnley on Saturday.
For much of Ferguson's 24-year reign at Old Trafford it has been Arsenal who have provided the main resistance to his empire-building and the old rivals go head to head with their title hopes at stake once again.
Ferguson fulfilled his ambition to knock Liverpool "off their perch" at the top of English football years ago and Chelsea have only emerged as serious challengers in recent years, but Arsenal, whether managed by Arsene Wenger or George Graham, have always been a thorn in United's side.
From the moment Arsenal defender Nigel Winterburn launched a tirade of abuse at Brian McClair following the United star's missed penalty in an FA Cup tie in 1988, there has been an extra edge to clashes between these super-powers.
The list of grudge matches is endless and endlessly entertaining: Roy Keane's tunnel row with Patrick Vieira; Martin Keown's frenzied celebration of a Ruud van Nistelrooy penalty miss and the Battle of the Buffet that saw Ferguson hit by pizza thrown by Arsenal players after a particularly spicy encounter are just a few of the more notable bust-ups.
Ferguson's strained relationship with Wenger has often provided these games with an intriguing sub-plot, but they are closer these days and happy to savour such a big occasion.
"These games with Arsenal are historic," Ferguson said. "Since I came down here, apart from the early years before George Graham won his first title, it was Arsenal and United who were mostly competing for the trophies.
"Without doubt Chelsea have become a prominent team in that respect too and it has been ourselves and Chelsea challenging for the league in the last few years.
"But you can never dismiss Arsenal because their history will always guarantee a challenge. And they are definitely in the fray again.
"Sunday's game has great relevance because both sides have a genuine chance of winning the league."
Wenger has always seemed more uncomfortable when the flak has been flying, but he would happily get under Ferguson's skin again because it would prove Arsenal are serious contenders once more.
His squad certainly looks capable of pushing United and Chelsea all the way after over-coming a lengthy injury list to erase an 11-point gap to the leaders.
Even without injured duo Thomas Vermaelen and Eduardo - both sidelined by knocks during the midweek draw at Aston Villa - Wenger is confident his players will rise to the occasion.
"I look forward to it because it is a match which always promises good football," Wenger said.
"Manchester United and Arsenal have had some tough games, and sometimes they were not easy on the physical side, but both teams always tried to play.
"It was very rarely a boring game, you always thought at the start it would be a great football game, and so you love that. It is always one of the games of the season."
Wenger will hand Sol Campbell his first league start since returning to the club. Nicklas Bendter or Samir Nasri will deputise for Eduardo, while Alex Song and Emmanuel Eboue are back from African Cup of Nations duty.
United will be without suspended defender Rio Ferdinand but that loss is offset by Serbian centre-back Nemanja Vidic's return from injury and Ferguson can also rely on in-form striker Wayne Rooney, who has 13 goals from his last 13 appearances.
With games against Chelsea and Liverpool to come, this is a defining period for Arsenal, but Wenger is just happy to be in the hunt again.
"We love being in the race. Of course it was our dream to be in this position," he said.
