Wayne Rooney has informed Manchester United he will not sign a new contract and wants to leave the club. With a squad of ageing stars and youngsters yet to prove themselves, there are fears his departure could put the club into decline, but this is far from unchartered territory for Ferguson.
ESPNsoccernet selects the First XI stars who left Ferguson's United.
Paul Ince (1995)
Following his hugely controversial arrival from West Ham in 1989, Ince became a key player for United as they began their dominance of the Premiership, but personality clashes dogged the midfielder, who insisted he be referred to as 'the Guv'nor'. In a documentary in 1998, Ferguson famously referred to him, less reverentially, as a "f***ing big-time Charlie".
"I was bothered by Paul's attitude around the dressing room," Ferguson wrote in his Managing My Life autobiography. "He'd attached a rather silly title to himself: 'Don't call me Incey, call me the Guv'nor'. That didn't go down too well. Paul had reached an age of maturity and this 'Guv'nor' nonsense should have been left in his toy box. It was quite apparent that he was completely carried away."
And so, while Ferguson had been "adamant" that Ince would not be sold, he allowed one of his stars to depart. He claimed Ince had been plotting his departure for months, with his representatives calling Inter president Massimo Moratti, and said: "I was not prepared to put up with all that crap. I phoned Paul from America and said, 'If you want to leave, leave, and if you want to stay, stay'. I honestly thought he wouldn't go and told him to sort himself out. There's a risk letting a great player go, but a lot of that's down to Ince."
Mark Hughes (1995)
Hughes had left United once before, in the summer of 1986, when he headed off to Barcelona. His sale had prompted a decline at Old Trafford, with Ron Atkinson's men - after finishing fourth in the 1985-86 season - enduring a dismal start to the new campaign, winning only one of their first nine league games. Atkinson was sacked the day after a 4-1 League Cup defeat to Southampton, with the club 19th in the table.
Ferguson replaced him in November that year and four months later had lifted the club to 11th, but he was having to play midfielder Norman Whiteside as a striker and was already set on trying to bring Hughes back to the club.
"If we could have him before the end of the season, it would be a great boost for the rest of the season," Ferguson said in March. Hughes outlined his determination to prove himself at Camp Nou but, after a loan spell at Bayern Munich, he returned to Old Trafford in 1988.
In his second spell, he helped United to two league titles, two FA Cups, a League Cup and the Cup Winners' Cup, but his status as a Welshman restricted his value given limits on foreigners in European competition. United eventually agreed to sell the 31-year-old to Chelsea, for £1.5 million, the day after the Ince deal.
Andrei Kanchelskis (1995)
After Ince had joined Inter and Hughes had departed for Chelsea, Ferguson and chairman Martin Edwards vowed that there would be no more sales that summer, but there was a terminal rift between Ferguson and Kanchelskis, his hugely talented winger.
"Every day fans knock on the door of my home and beg me to stay," Kanchelskis said. "My heart is with Manchester United but I can't stay for one reason and that is the manager. Our personal problems are just too big."
Everton snapped up Kanchelskis that July, and fans became incensed with Ferguson and the club, with Andy Walsh, the secretary of the Manchester United Independent Supports Association, saying: "Sadly, the supporters of Manchester United have grown accustomed to seemingly unfathomable decisions being made by the club's hierarchy."
Ferguson was subsequently linked with a "move upstairs" ahead of the 1995-96 season, and Alan Hansen famously warned in August that they would "win nothing with kids", but Fergie's Fledglings won both the league and FA Cup that season.
Eric Cantona (1997)
Perhaps the greatest loved United star of the Ferguson era, Cantona's defection from fierce rivals - and then league champions - Leeds United in 1992 was the catalyst for the glory years that followed.
United were crowned champions in four of his five seasons at the club and he had become such an iconic figure that, in April 1997, church leaders were moved to speak out against an "offensive and blasphemous" painting in Manchester City Art Gallery that depicted him as Jesus Christ.
Later that month, following the Champions League semi-final exit to Borussia Dortmund, Cantona - 30 years old - informed Ferguson he did not wish to see out the final year of his contract. Martin Edwards swiftly moved to dismiss the talk - "There is no issue," he said, "no justification for that kind of speculation" - but the player's resolve did not waver, and his decision was confirmed on May 18.
The first hint of a departure had come after his winning goal in the 1996 FA Cup final, when he said he would "stay at Old Trafford for two more years ... maybe longer or maybe shorter", but even for a man so unpredictable, his decision had caught many off-guard. He had, he explained, "always planned to retire at the top".
Ferguson described the news as a "sad day for United", but one of his predecessors, Tommy Docherty, struck a more resilient tone. "Nobody is irreplaceable," he said. "The king is dead - long live the king. Somebody will always come along."
Peter Schmeichel (1999)
Schmeichel left United after the Treble success of 1999, with United's dramatic comeback against Bayern Munich in the Champions League providing his final moments, but as he had reached his mid-30s, he felt obliged to step back from the rigours of English football.
"I need more time between games than I can get in England," he said in November 1998. "[It] is something I truly regret."
He joined Sporting, with Ferguson describing his departure as a "terrible wrench", and he was, as his manager predicted, very much "missed" at the club. Mark Bosnich, Fabien Barthez and Tim Howard were all brought in as replacements before Edwin van der Sar, in 2005, finally made the role his own.
Jaap Stam (2001)
Signed from PSV in 1998, Stam was a roaring success at Old Trafford until his shock sale to Lazio in 2001.
That was the year his autobiography, Head to Head, was serialised in the Mirror, detailing his description of the Neville brothers as "busy c****" as well as the revelation that Ferguson had approached him without PSV's permission.
Ferguson has insisted that the £16.5 million sale of the 29-year-old was motivated by its value to the club, rather than his remarks, but he said in 2007: "In playing terms, it was a mistake. He is still playing for Ajax at a really good level."
The ageing Laurent Blanc struggled to fill his boots, and Stam said he "always knew" Ferguson had made a mistake. "I know this is the same feeling for many people around the club, from colleagues to fans," he added.
David Beckham (2003)
Eric Cantona's successor in the No. 7 shirt at United, Beckham had become a global superstar both for his efforts on the field and his celebrity lifestyle - Spice Girls, sarongs and all - off it.
Ferguson had been impressed by Beckham's dedication to the game at an early age and had tried to protect him from too much media hype. After his legendary goal against Wimbledon in August 1996, Ferguson labelled it the "goal of the season already", but stressed that "David is young and there is a long way to go yet".
Just 21 at the time, Glenn Hoddle then called him into the England squad and said: "I understand Alex Ferguson wants to be protective, but listening to the boy and working with him, I know he has a level head. He's not too flashy."
The following year, he began dating Victoria Adams and, two years later, they wed, selling the rights to the ceremony to OK! magazine. Beckham's relationship with his manager had begun to sour, with Ferguson - who has regularly championed marriage as a means of settling players down - unhappy at the influence of his celebrity wife. "He was never a problem until he got married," Ferguson said in 2007.
Their relationship reached a nadir in 2003, when the infamous flying boot incident saw the duo dominate the front pages of the newspapers and eventually led to his sale to Real Madrid that summer.
Roy Keane (2005)
While he was on the wane at the time of departure, 34-year-old Keane remained the standard bearer among players at the club.
It was his demands on others that sparked the end of his ailing relationship with Ferguson as he hit out at the likes of Rio Ferdinand, Darren Fletcher, Alan Smith and John O'Shea during an appearance on MUTV's 'Play the Pundit' show.
The rant had come as United looked a side in crisis, with fans unveiling a banner imploring Ferguson to quit.
Keane walked out on November 18, apparently after an argument with Carlos Queiroz, and there were severe concerns given the quality of signings in the position in recent years, notably Kleberson and Eric Djemba-Djemba. Michael Ballack and Gennaro Gattuso were touted as replacements, but in the end it was left to the likes of Fletcher, Smith and O'Shea to fill the void.
Ruud van Nistelrooy (2006)
PSV striker Van Nistelrooy's move to United in April 2000 had ground to a halt over issues raised by the medical and, a day later, he suffered a cruciate knee ligament injury that put him out of action for nine months.
Ferguson, though, kept in contact with the striker, visiting him in hospital and, in October, inviting him to train with the club. The PSV chairman, Harry van Raaij, was incensed by this "stupid" invitation, accusing Ferguson of "thinking he is the king of football," but the £19 million deal was completed in April 2001 and Van Nistelrooy had been touched by Ferguson's support.
He became one of the deadliest strikers in the club's history after his move, but the pair fell out when he was benched for the 2006 League Cup final against Wigan due to the form of Louis Saha.
"I exploded and began swearing at Ferguson because I felt he had kicked my soul," Van Nistelrooy later said of the incident. "That was the moment things died and could never be the same again. This was the man who visited me in hospital when I had my bad knee injury while I was with PSV. This was the man who wanted me at all costs."
Van Nistelrooy joined Real Madrid that summer.
Cristiano Ronaldo (2009)
The saga surrounding Ronaldo's departure cast a long shadow over the club. A player Johan Cruyff rated better than George Best and Denis Law, Ronaldo scored 42 goals in all competitions in the 2007-08 season as United clinched the Premier League and Champions League.
Yet it became clear over the course of the following season that Ronaldo was already eyeing his next challenge. Occasional proclamations of loyalty to his club muddied the waters while, in December 2008, Ferguson dismissed Madrid's claims a deal was in place. "Do you think I would enter into a contract with that mob?" he said. "I would not sell them a virus."
He did sell Cristiano Ronaldo, though, to Calderon's successor, Florentino Perez, accepting a world-record £80 million fee on June 11.
Carlos Tevez (2009)
While it had not been unexpected, the news of June 20 that Carlos Tevez would not prolong his stay at Old Trafford - despite United's offer to make him "one of its highest paid players" - proved a double blow after the Ronaldo announcement.
"I was there for two years and Sir Alex never called me or sent me a text," Tevez said. "I don't think that's a great way to treat a player."
A bit-part player in comparison to Rooney and Ronaldo, Tevez had nonetheless been one of the biggest stars at the club. Wigan's Luis Antonio Valencia was the most significant arrival that summer, and it was left to Rooney to lead United's bid for domestic and European success side the following year.
Had Rooney not sustained an ankle injury in the Champions League quarter-final first leg against Bayern Munich, events may have turned out differently, but they ended the year with only the League Cup, little more than a consolation prize by the club's lofty standards.