After three seasons of great success were interrupted in 2009-10, Sir Alex Ferguson needs the key members of his squad to stay off the treatment table if they are to wrest the title back from within the grasp of Chelsea and hold off the challenge of big-spending neighbours City.
A crippling injury list ruined United's chances of claiming their record 19th title last season and with Owen Hargreaves, Rio Ferdinand, Nemanja Vidic, Paul Scholes, Michael Carrick, Edwin van der Sar, John O'Shea, Anderson, Wes Brown, Gary Neville and Michael Owen all out for long periods, Ferguson's side must overcome their injury curse if they are to challenge again.
Unfortunately for the former champions is that they will have to start the new season without Hargreaves, Ferdinand, Anderson or Owen, but there are plenty of squad players willing to fill the gaps. Last season, the club were forced to rely on midfielders Darren Fletcher and Carrick to cover at right-back and centre-half and Ferdinand's injury niggles this summer suggest that they may be called into service at some point again.
With no big-name new signings joining the club, United have been linked with bids for Slovakia's Marek Hamsik and Dutchman Wesley Sneijder - to add creativity to the midfield - and Italian defender Giorgio Chiellini - to bolster the backline - but none have been forthcoming.
Indeed, Ferguson has maintained that he is happy with his squad after the simple additions of Chris Smalling and Javier Hernandez. Money, even with the ever-increasing debt imposed by the Glazer family, is supposedly not a problem but England Under-21 international Smalling may find himself having to learn fast.
Despite all the injuries, United's defence was still the meanest in the league last season - conceding just 28 goals - and Smalling showed during his one season (and 13 games) in the spotlight at Fulham that he has the potential to rise to the occasion should Jonny Evans and Wes Brown find themselves on the sidelines again.
The versatility of John O'Shea was much missed after he picked up an injury playing for Ireland against France in November, and his absence during a crucial part of the season around Christmas played its part in United's failure to overhaul Chelsea at the top. Now 29, O'Shea may not warrant a first-team place, but his experience and attitude place him among Fergie's favoured players to call upon in a crisis.
The others on that list, United's 'Old Guard', will be key as the squad is stretched by injury and fatigue. But Ferguson faces a new challenge this season: finding suitable replacements for the players who have served him so well through the past decade and a half.
Without the investment that many fans were expecting, the players stepping into the boots of Gary Neville, Ryan Giggs and Paul Scholes are just those... a trio with a combined age of 106. However, Ferguson has pinpointed youngsters for the future for whom this season will be about convincing the manager that they are worthy of place in the side.
At right-back, Rafael has been tipped for greatness for some time and has surpassed his twin brother, Fabio, in claiming a first-team spot. However, despite his pace, stamina and skill on the ball, he has shown lapses of concentration and an immaturity that has had serious consequences. His sending off against Bayern in the Champions League quarter-finals helped the Germans seal their progress on away goals and will live long in the memory. He still has much to prove.
Ryan Giggs is virtually irreplaceable as a player who has won more silverware than any other in the English game, but Ferguson's signing of Gabriel Obertan was designed to help the Welshman's transition into retirement. Obertan should be given more chances to shine in the coming season, but with Antonio Valencia, Park Ji-Sung and Nani progressing well on the wings - and Giggs still used to good effect - he will find the route tough to navigate.
As Giggs has aged, he has drifted into a more central role and that has suited Ferguson as United are not blessed with much creativity in the middle. Scholes' natural replacement, Brazilian Anderson, has not lived up to expectations and the fans may worry that Darron Gibson, Carrick and Fletcher are not up to the job of pulling the strings. Without a Hamsik or a Sneijder, Fergie will rely again on Scholes (or the youth of Tom Cleverley) to take control and, as he has become more inconsistent with age, that could be a dangerous gamble.
With those worries already on his plate, replacing soon to be 40-year-old Edwin van der Sar in goal could be left until next season. Selling Ben Foster was a sign of faith in No.2 Tomasz Kuszczak, with youngster Ben Amos promoted to the third-choice position and, although it remains an area requiring an overhaul, United's goalkeeping situation will remain stable for now.
However, at the other end of the pitch, Ferguson faces a different dilemma; he has the unenviable task of lifting Wayne Rooney out of his post-World Cup slump. The striker scored 26 in 32 games in the Premier League last season, but looked woefully short of form and fitness in South Africa and, given that his goals lifted United through some tough spells, the club need their star man to hit the ground running.
If he doesn't fire from the start, at least Fergie has a potential star in Mexican striker Hernandez - a £10 million summer addition - to call upon. Scoring 17 goals less than Chelsea last season, it was notable that Own Goal finished second top scorer alongside Dimitar Berbatov (with 12). The new boy, who has earned comparisons to legendary predator Ole Gunnar Solskjaer from his boss, already looks a far more dangerous proposition than Michael Owen or the lethargic Bulgarian put together.
Ultimately, with one of the biggest squads in the league, the manager's toughest task could be to trim down his players to the required 25. Keeping his players fit throughout the season should ensure, once again, that they are challenging at the top but surely the motivation of finishing above the ''noisy neighbours'' of City will be all that Ferguson and his old guard need.