Manchester City's attempt to progress beyond the group stage for the first time continues when they host champions Bayern Munich while Russian pair CSKA Moscow and Zenit St Petersburg will both attempt to collect their first point.
Swiss champions FC Basel, who provided the only shock of the opening matches by winning at Chelsea, could also upset Schalke 04 if they can make the most of the Bundesliga team's leaky defence and Celtic will attempt to repeat last year's upset home win over Barcelona.
Possibly the week's most intriguing game is in highly competitive Group F where Arsenal host Rafael Benitez's Napoli, who began with a 2-1 home win over last season's runners-up Borussia Dortmund and are still unbeaten in all competitions under the Spaniard's leadership.
Four-times champions Ajax, thumped 4-0 by Barcelona in their opening Group H match, used to be one of Europe's top clubs but can no longer compete with the financial clout of teams from the big five European leagues.
The Dutch champions, whose coach Frank de Boer played in their 1-0 win over AC Milan in the 1995 final, have been reduced to a club that develops young talented players and sells them on.
They have been knocked out in the group stage on their last three appearances, suffering 4-1 home defeats by Real Madrid and Borussia Dortmund last season, and have not reached the round of 16 since 2005-06.
AC Milan, who won the last of their seven European Cup and Champions League titles in 2007, have been struggling to rebuild since offloading a number of top players one year ago.
They have had a terrible start to this season, picking up only two Serie A wins in six games and scraped past Celtic 2-0 in their opening Champions League match. New signings Riccardo Saponara and Kaka have both suffered injuries.
Milan and Barcelona are expected to progress from the group, although the Catalans will not be looking forward to visiting Celtic where they lost 2-1 last year.
Group D looks straightforward with Manchester City and Bayern Munich, who both won their opening games 3-0 against CSKA Moscow and Viktoria Plzen respectively, clear favourites to progress regardless of the outcome of Wednesday's match.
Big-spending City's first two Champions League appearances ended in group stage elimination but their convincing win in Plzen and the vast European experience of coach Miguel Pellegrini suggest they will do better this time.
CSKA host Plzen in the other game and the Czech champions, making their second appearance, have already learned some painful lessons.
"We were chasing them on scooters, while they were driving Ferraris," said defender David Limbersky after the home defeat by City.
"We cannot afford a poor pass in midfield that allows the opposition a chance to go three on two, or three on one, on the counterattack," added coach Pavel Vrba
CSKA's compatriots Zenit host group stage debutants Austria Vienna in Group G, where both teams are aiming to get off the mark after opening day defeats, while Porto host Diego Simeone's Atletico Madrid in a battle for the group leadership.
Anything could happen in Group B where Basel, who eliminated Manchester United two seasons ago, are at home to Schalke, who have conceded 16 goals in seven Bundesliga games and squandered a 3-1 lead in a 3-3 draw at Hoffenheim on Saturday.
Crestfallen Chelsea, meanwhile, travel to Romanian champions Steaua Bucharest, where they lost 1-0 in the Europa League last season and where another defeat could point them towards the exit door.
Manchester United, who began with a 4-2 win over Bayer Leverkusen in Group A, face arguably their most difficult match of the group when they visit Shakhtar Donetsk in Ukraine.
Brazilian-inspired Shakhtar, who still appear to be a force to be reckoned with despite having to rebuild their team over the last few months, began well with a 2-0 win at Real Socieded.
Juventus, at home to Galatasaray, and Real Madrid, who host FC Copenhagen, should sail through their games in Group B while big-spending Paris St Germain host twice former champions Benfica in Group C.