Arsenal, who visit Besiktas, will be aiming to reach the lucrative group stage for the 17th consecutive season while Slovan Bratislava, Ludogorets Razgrad and Malmo are all trying to qualify for the first time.
Millions of euros are at stake for the clubs involved in this week's 10 matches, thanks to the huge appearance fees, performance bonuses and television money handed out by Uefa to those who reached the group stage.
Last season, Uefa awarded each of the 32 teams ?8.6 million (about R91-million) just for taking part in the group stage, with more thrown in for wins and draws.
Napoli's participation last season brought them ?38.6-million, including ?4-million in the so-called performance bonuses and ?26-million of their share of the television market pool.
Failure to beat Athletic, Europa League runners-up in 2012, could put immediate pressure on Napoli coach Rafael Benitez, whose debut season last season was regarded as only satisfactory.
"Among the five possible opponents, with Athletic we have been landed with the most difficult," warned Benitez.
"They're a team who play good football and, at home, the 50000 at San Mames give them a big push. It will be a very good, and very intense game."
Arsenal visit Besiktas in Istanbul tonight, although last season's 5-0 aggregate win over Fenerbahce suggests they should be able to cope with the Turks.
Slovan Bratislava from Slovakia host Belarus champions Bate Borisov tomorrow.
Malmo, runners-up in the old European Cup, visit Austrian champions Salzburg hoping to become the first Swedish team to qualify for 14 years.
Belgium midfielder Axel Witsel will return to his old club with Zenit St Petersburg when the Russians visit Standard Liege tomorrow.