Arsenal, who visit Besiktas, will be aiming to reach the lucrative group stage for the 17th consecutive season while, at the other extreme 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 euros 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 euros, including 4 million in the so-called performance bonuses and 26 million euros 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.
A third place Serie A finish and the Coppa Italia title were the bare minimum expected from the Spaniard at Italy's biggest-spending club who performed only in fits and starts last term, repeatedly dropping precious Serie A points against lower-placed opposition.
"Those two matches can shape a season because it's true that the Champions League provides a different dimension to the club, the city and to us players," said Napoli forward Marek Hamsik.
"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 50,000 at San Mames give them a big push. It will be a very good, and very intense game."
Arsenal will have played one Premier League match before they visit Besiktas in Istanbul on Tuesday, although last season's 5-0 aggregate win over Fenerbahce suggests they should be able to cope with the Turks.
Slovan Bratislava host Belarus champions BATE Borisov on Wednesday as they attempt to emulate MSK Zilina, MFK Kosice and Petrzalke by representing Slovakia in the group stage.
Ludogorets Razgrad begin their attempt to become only the second Bulgarian side to qualify when they visit former European champions Steaua Bucharest on Tuesday.
Malmo, runners-up in the old European Cup, visit Austrian champions Salzburg on Tuesday, hoping to become the first Swedish team to qualify for 14 years.
Salzburg themselves have not qualified since the takeover by the Red Bull energy drinks manufacturers in 2005 although they did qualify in 1994-95, back in the old days when they still played in violet and white.
Belgium midfielder Axel Witsel will return to his old club with Zenit St Petersburg when the Russians, led by Portuguese coach Andre Villas-Boas, visit Standard Liege on Wednesday.
Ambitious Zenit, whose new signings included Argentina World Cup defender Ezequiel Garay, have made a flying start to the Russian Premier League, winning their first four games and beating Torpedo Moscow 8-1 in the process.
Group stage regulars Porto, the club where Villas-Boas made his name, have a tough trip to Lille while Celtic, who like Porto are former European champions, visit Slovenian champions Maribor, provided the Court of Arbitration for Sport (CAS) does not intervene.
Celtic were thrashed 6-1 on aggregate by Legia Warsaw in the previous round, only for the Poles to forfeit the second leg after fielding an ineligible player in the last few minutes.
UEFA turned Legia's 2-0 win at Murrayfield into a 3-0 win for Celtic, which sent the Scottish champions through on away goals.
Legia have appealed to CAS who are due to announce on Monday whether they will grant "provisional measures" which would allow the Polish champions back into the draw.
Denmark have a chance to have two teams in the group stage for the first time as FC Copenhagen host Germany's Bayer Leverkusen on Tuesday with Aarborg at home to APOEL, surprise quarter-finalists two seasons ago, on Wednesday.
The second legs will be played on Aug. 26 and 27 with the draw for the group stage taking place in Monaco on Aug. 28.
Napoli 10-11, Athletic Bilbao 7-2, Draw 13-5
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