Manchester United midfield target Reus is the latest casualty in a growing list of players who won't be playing in Brazil. And several other superstars are fighting hard to be fit for the tournament.
Reus damaged ankle ligaments in Germany's convincing 6-1 victory over Armenia. The Dortmund midfielder has been on scintillating form of late, and his omission from the squad will be a huge loss for Joachim Low's side. The injury may also hamper Reus' chances of securing a move away from Germany to the Premier League as he returns to full-fitness.
Manchester United remain favourites for his signature if he does, however, come to England. The player scored 21-goals and 15-assists for Borussia Dortmund last season.
And Franck Ribery's World Cup dream is over. The French winger hasn't been able to overcome a prolonged back injury. France manager Didier Deschamps will be aggrieved by the news of the Bayern Munich man's omission. 31-year-old Ribery has clocked up 81-caps for his country, and probably feels he has missed his last opportunity to play at a World Cup.
The former Marseille-man described his withdrawal from the French squad as 'soul-destroying. Ribery's absence means that Southampton centre midfielder Morgan Schneiderlin will come in as a late replacement.
Elsewhere, Columbia will have to make do without big-name striker Radamel Falcao, after he pulled out of the World Cup with a serious knee-injury. The former Chelsea target's absence will be a huge blow for the South American side, who currently sit 8th in the FIFA World Rankings.
While some players will certainly miss out on Brazil, there a few who still may make it, but remain doubtful of playing in the opening games.
Alex Oxlade-Chamberlain is testing the nerve of England manager Roy Hodgson, after a seemingly innocuous challenge by Ecuador's Carlos Gruezo on Wednesday left the Arsenal midfielder's chances of playing in England's opener against Italy in doubt.
Chamberlain struggled with injuries last season and was hampered by a long-season lay-off. Since his return to injury, however, the Arsenal man impressed and was given the nod by Hodgson.
Meanwhile Cristiano Ronaldo is also a major doubt to make Portugal's opening game against Germany, as he is suffering from tendinosis in his knee. Portugal's medical staff will be doing all they can to ensure the Ballon D'or winner will be ready in time to captain his country.
Finally, Uruguay will be keeping their fingers crossed that on-form Luis Suarez will be able to play a part in Brazil on his return from injury. Suarez was in prolific form last season, nearly averaging a goal-a-game.