Mazembe,from the Democratic Republic of Congo, host Simba of Tanzania as the second qualifying round begins, and Ahly of Egypt have the home advantage over SuperSport United of South Africa.
There are ten other former winners in action and only two come into direct contact with the clash between Club Africain of Tunisia and Zamalek of Egypt, the major attraction of a 15-fixture schedule.
Since crushing Esperance of Tunisia 6-1 over two legs last November to become the first club to successfully defend the title twice, Mazembe finished runners-up behind Inter Milan in the FIFA Club World Cup.
But a never-ending domestic and international fixture list began to tell two months ago when the 'Crows' struggled to a penalty-shootout victory over FUS Rabat of Morocco to retain the African Super Cup.
A DR Congo squad stacked with Mazembe stars then flopped when defending the African Nations Championship title in Sudan and goalkeeper Muteba Kidiaba admitted his team-mates desperately needed a break.
Stars like leading scorer Dioko Kaluyituka got some respite in the shape of a first-round Champions League and playing at the Municipal Stadium in Lubumbashi offers the chance to establish a tie-winning lead.
Simba are regular but largely unsuccessful African campaigners who did not impress in the previous round, taking 161 minutes to get on top of minnows Mitsoudje from the Comoros Islands.
But Zambia-born coach Patrick Phiri is nothing if not an optimist.
"I have a squad capable of defeating any team in the Champions League," he boasted after reaching the last-32 stage.
The popular uprising against long-time Egypt ruler Hosni Mubarak halted competitive football in the country during January and Ahly have been playing friendlies in Saudi Arabia.
Greying Portuguese magician Manuel Jose is back for a third spell as Ahly coach after Hossam al-Badry quit following a controversial semi-finals exit last year, with a deliberate hand-ball goal taking Esperance through.
SuperSport will lack suspended Liberian striker Anthony Laffor and the difficulty they experienced in disposing of Lesotho side Matlama suggests 90 torrid minutes against stars like Mohamed Aboutreika and Mohamed 'Geddo' Nagy.
Zamalek and Egypt defender Mahmoud Fathallah believes the Tunis showdown with 1991 winners Club Africain has come too early in the premier Pan-African club competition.
"The draw is unfair as both teams are experienced and capable of competing for the title. Whoever goes through will have consumed a lot of energy by the time they secure qualification," he warned.
Revitalised by the coaching of former national star Hossam Hassan, five-time champions Zamalek are considered strong contenders for a first title since 2002 and their performance in Tunisia will be illuminating.
Other former champions in action are Entente Setif and Mouloudia Alger of Algeria, Raja Casablanca and Wydad Casablanca of Morocco, ASEC Mimosas of Ivory Coast, Enyimba of Nigeria, Esperance and V Club of DR Congo.