Nigeria hosting South Africa in Group E is the standout fixture as 47 countries begin the group stage of qualifying for the 2019 Africa Cup of Nations in Cameroon.
Another big clash this weekend is the north African clash between Tunisia and Egypt in Group J.
The 12 group winners will qualify along with the best three runners-up will join hosts Cameroon in the finals.
South Africa are looking for a first win in an official match over Nigeria since 1992 after six losses and three draws.
The Super Eagles are aiming to qualify for the Nations Cup finals for the first time since winning the title in 2013.
"We do not want to forget that South Africa partly contributed to us not going to the 2015 Cup of Nations," said Nigeria's stand-in captain Ogenyi Onazi.
"This time, we must restore our pride and make sure we get the three points off them on Saturday.
"Nigerians do not forgive losers easily and it is our responsibility to make the country proud whenever we are in action."
Defender Thulani Hlatshwayo, who plays South African champions Wits, was named Bafana Bafana captain this week by new coach Stuart Baxter.
"It will be a baptism of fire as captain, but we have come close to beating them in our last two meetings and I think they are there for the taking this time," he insisted.
"I believe we have now overcome that psychological barrier of not having beaten them in an official match.
"This will be a grudge match. We denied them a place at the 2015 Cup of Nations and they will be out for revenge, which might work to our advantage."
Nigeria's German coach Gernot Rohr cautioned against over-optimism after he lead the Super Eagles to 2018 World Cup qualifying wins over Zambia and Algeria.
"Our team is young and the future looks bright, but there is still considerable work to do," he said.
Baxter begins a second stint in charge of "Bafana Bafana" in a confident mood despite the loss through injury of key midfielder Hlompho Kekana.
"We are capable of hurting Nigeria. We want to be a big nuisance to them - to be their worst nightmare," the Englishman insisted.
Tunisia host seven-time African champions and 2017 runners-up Egypt in the final tie of the weekend on Sunday evening.
Al Ahly and Zamalek dominate the Egypt squad with 14 of the 25 players, but Argentine coach Hector Cuper can also rely on several Europe-based 'Pharaohs'.
Mohamed Salah was a consistent scorer in Italy for Roma last season.
Ivory Coast will dedicate a Group H clash with Guinea in Bouake to the memory of 2015 Nations Cup winner Cheick Tiote, who died in China this week.
New Elephants' coach Marc Wilmots had a nightmare debut last Sunday with a 5-0 friendly drubbing by the Netherlands - a record Ivorian loss in their 57-year history.
Although guaranteed a place at the 2019 finals as hosts, title-holders Cameroon play in Group B and host Morocco in Yaounde.
Points won by Cameroon's opponents in the qualifying will count towards their final totals in the group.
Another nation with a new captain is Zimbabwe as Knowledge Musona leads a new-look Warriors side against visiting Liberia in Sunday's Group B match.
The Belgium-based striker takes over from Willard Katsande, who was skipper at the Nations Cup finals in Gabon earlier this year.
Former captain Norman Mapeza is Zimbabe's interim coach and he has not selected many of the players who featured in Gabon.
"It's not a bad team, I've played with most of the guys," Musona insisted.
"It would be something else to lead the team to qualify.
"It's a tough group but you never know in African football, and we need to make a good start and apply our tactics and play our game and work hard as a team.
Zimbabwe are in Group B with Liberia, DR Congo and Congo-Brazzaville, and are targeting a fourth appearance at the Nations Cup finals.
Source: BBC