Arsenal and AC Milan face daunting Champions League dates in mid-week as 20 teams chase the 10 remaining places in the world's most lucrative club competition.
Arsenal, runners-up in 2006, have a series of fitness worries ahead of their tricky trip to Istanbul to face Fenerbahce on Wednesday.
Alex Oxlade-Chamberlain and Kieran Gibbs both went off injured in the first half of their 3-1 home defeat to Aston Villa on Saturday while right-back Bacary Sagna also had to be replaced after falling awkwardly on the back of his neck late on.
They were already without midfielder Mikel Arteta while centre-back Thomas Vermeulen and full-back Nacho Monreal both missed Saturday's clash with back problems.
It is in defence that Arsenal are most vulnerable and their absentees in that department could cost them dearly, particularly with former Chelsea nemesis Didier Drogba likely to line up opposite them.
Arsenal midfielder Jack Wilshere said the club must rebound quickly.
"We're not happy, we've got to look at ourselves," he said. "We've got a big qualifier coming up and there can be no mistakes now, we've got to push on. We've got to pick ourselves up."
Adding spice to Wednesday's clash is that Fenerbahce's potential participation in the group stage, should they get through, depends on a ruling from the Court of Arbitration for Sport, expected at the end of the month, having been banned from European competition by UEFA for match-fixing in domestic competition.
It will be a baptism of fire for AC Milan as the Italians start their season with a trip to PSV Eindhoven on Tuesday.
While the Dutch outfit have already played five matches, including the Champions League third qualifying round in which they thumped Belgians Zulte-Waregem 5-0 on aggregate, Milan have yet to take to the field competitively as Italy's Serie A does not kick-off until this coming weekend.
It means a daunting trip to Holland for Massimiliano Allegri's men to tackle a side that have won every match they have played this season, scoring 16 goals in the process and conceding only two.
PSV's attacking prowess will be a concern to Milan who had a mixed bag in pre-season, including conceding five goals to Manchester City in a friendly in Germany, while they also lost games against Chelsea and Juventus, although they did beat Spaniards Valencia and Brazil's Sao Paolo.
The good news for Milan is that Italy striker Mario Balotelli looks set to start despite missing last week's international friendly against Argentina.
The importance on reaching the Champions League group stages has not been lost on goalkeeper Christian Abbiati.
"For Milan, participating in the Champions League is fundamental. Milan don't exist without the Champions League," he told Sky Sport earlier last week.
Milan last missed out on the Champions League group stages in 2008/09 having finished only fifth in Serie A the previous season and Allegri, who was under fire for most of last season, will know that anything other than progress against PSV will likely cost him his job.
In other first leg games Schalke 04 have had to change their preparation at the last minute with Greek side PAOK replacing their original opponents Metalist Kharkiv, with the Ukrainians having been banned over a match-fixing scandal in their homeland.
Metalist had knocked out PAOK in the third qualifying round but the Greeks were offered a reprieve by their opponents' ban.
Portugal's Pacos Ferreira will be looking to make history as they host Russians Zenit St Petersburg, the 2008 Europa League winners.
Pacos had never finished higher than sixth in the Portuguese league until their third place last season earned them this opportunity of a first ever Champions League appearance.
Bulgarians Ludogorets Razgrad are also looking for a debut group stage appearance as they host Basel.
Ludogorets had never even won a European game until this season.
Scottish champions Celtic face the long trip to Kazakhstan to face Shakhter Karagandy on Tuesday.