Orlando Pirates of South Africa must win, Ahly must win and get help, and fellow Egyptians Zamalek need a draw to secure CAF Confederation Cup semi-finals places this weekend.
New Egyptian champions Zamalek are the second most successful club behind Ahly in Confederation of African Football (CAF) competitions with nine titles, but the last came 13 years ago.
That could be about to change as the Cairo White Knights have taken control of Group B with three consecutive victories, including an impressive come-from-behind triumph away to Pirates.
Zamalek have nine points after three matchdays, Pirates six, and three-time title-holders CS Sfaxien of Tunisia and shock 2012 Confederation Cup winners AC Leopards of Congo Brazzaville just one apiece.
Experienced Portugal-born Zamalek coach Jesualdo Ferreira has moulded young and experienced footballers into a potent force that last week ended the 11-year domestic league dominance of Ahly.
Now the Knights want to succeed Ahly as winners of the Confederation Cup, the second-tier CAF club competition that offers a $660,000 (610,000 euros) first prize.
"I greatly admire the fighting spirit of my players," said former Porto boss Ferreira.
"They play two matches most weeks, but are always competitive whether it is a domestic or African game."
Having achieved a comfortable 2-0 win over Leopards in Cairo two weekends ago, they travel to Dolisie to face the same opposition.
It is likely to be tougher for Zamalek in central Africa, not least because the Stade Denis Sassou Nguesso pitch is hard, bumpy and not conducive to the passing game the Cairo outfit favour.
One starter in Egypt who will miss the return match is experienced Leopards African campaigner Rudy Guelord Bhebey-Ndey.
The Congolese striker suffered multiple serious injuries after falling awkwardly early in the match and is recovering afer life-saving surgery in a Cairo military hospital.
Pirates won in Congo on matchday 1, so a Zamalek side boasting stars like goalkeeper Ahmed El Shenawy, leading scorer Bassem Morsy and rising Nigerian star Maarouf Youssef will be confident.
And so will Pirates, the only South African club to be crowned African champions, who are seeking another win over Sfaxien after a 1-0 victory in Tunisia via an exquisite Thabo Rakhale goal.
However, the Soweto Buccaneers must be wary against desperate opponents having developed a habit of home losses, with the Zamalek reverse followed by a domestic cup defeat at Orlando Stadium this week.
"Sfaxien are a very good team and we expect them to come at us because their Confederation Cup survival hinges on winning this game," warned Pirates coach Eric Tinkler.
Ahly, whose 97th-minute goal snatched the 2014 Confederation Cup from Ivorians Sewe Sport, triumphed 1-0 at home to Etoile Sahel and an away victory over the Tunisians would lift them to 10 points.
That would guarantee the Cairo Red Devils a top-two Group A finish provided Stade Malien of Mali do not win at home against Esperance of Tunisia, surprise losers when the sides met two Saturdays ago.
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