The 2013 Africa Cup of Nations kicks off on January 19 when hosts South Africa tackle Cape Verde in Johannesburg and few sides in the English top flight will have their squads untouched by the competition.
Defending champions Manchester City already have a seven-point gap on leaders Manchester United to chase down and their cause will not be helped by the absences of brothers Kolo and Yaya Toure, who play for the Ivory Coast.
Yaya, 29, was the driving force behind last season's title success but his absence for the 2012 Cup of Nations coincided with a spell that saw City eliminated from the League Cup by Liverpool, knocked out of the FA Cup by United, and beaten 1-0 by Everton in the league.
His elder brother, Kolo, has enjoyed a more prominent role this season, having established himself as the first-choice deputy to centre-backs Vincent Kompany and Matija Nastasic, and City are loath to lose both men.
"I'm not too sure how many games he (Yaya) is gone for but it's something we have known about and will have to deal with," said assistant manager David Platt.
Adapting to life at Chelsea
"We lost him last year and won the league. The kind of player he is, it would be more beneficial to have him, and it's similar with Kolo.
"But we will get on with it. It's like an injury – you want the full complement to choose from. We have a dressing room full of quality players and we have to cope with it."
The Ivory Coast's qualification will affect clubs at all levels of the table.
As well as the Toure brothers, Wigan Athletic stand to lose top scorer Arouna Kone and Newcastle United will be without key midfielder Cheick Tiote, while Arsenal lose Gervinho.
However, Senegal's failure to qualify means that Demba Ba will be free to focus on adapting to life at Chelsea, while his former Newcastle team-mate Papiss Cisse will be staying put at St James' Park.
Morocco coach Rachid Taoussi, meanwhile, has smiled on Queens Park Rangers and West Ham by overlooking mercurial QPR midfielder Adel Taarabt and the Hammers' on-loan Arsenal striker Marouane Chamakh.
Chelsea will lose Nigerian pair John Obi Mikel and Victor Moses, both of whom have emerged as key first-team players under interim manager Rafael Benitez.
Former Wigan winger Moses started nine of the first 13 games after Benitez arrived on November 21, while the impact of Mikel's absence will be exacerbated by the fact fellow holding midfielder Oriol Romeu has been ruled out for six months with a knee injury.
Confusion surrounded the participation of Tottenham Hotspur striker Emmanuel Adebayor, who was named in the Togo squad for the competition despite his differences with the Togolese Football Federation.
Adebayor has had to play second-fiddle to Jermain Defoe at White Hart Lane this season, but although his absence would leave Andre Villas-Boas with only one true striker at his disposal, the Spurs manager is happy for him to go.
"It was always his choice. I'm not going to put pressure on him," Villas-Boas said last month.
"We've left it to the player to decide. If the player wants to go, we respect the African Nations Cup."
The reach of the continental showpiece tournament stretches down to the lower reaches of the English league system, with Dean Furman of third-tier strugglers Oldham Athletic having been handed a call-up by South Africa.
"You see it every year," the 24-year-old told BBC Radio Manchester.
"Players all over are missing games. That is a difficulty, but when your country comes calling, it's very hard to turn down." – Sapa-AFP