With 39 Grand Slam titles and three Olympic gold medals between them, the tennis legends are aiming for more history in Cape Town
While the two men have won tournaments galore, both are also praised for their endeavours to raise money for disadvantaged children.
Swiss Federer holds the record for men's singles Grand Slams with 20, one ahead of Nadal.
The Spaniard has 12 French Open titles, the most for any player in a single Slam, while Federer has eight Wimbledon crowns.
Nadal is also ahead in the Olympic medal count with two golds to Federer's one gold and a silver.
The pair are hoping to make more history on Friday (7 February) by attracting the highest attendance for a tennis match at 'The Match in Africa'.
They are playing in Cape Town, South Africa with more than 50,000 spectators expected.
The current record was set last November in Mexico City's 'Plaza de Toros Mexico' bullring when 42,217 watched Federer play German ace Alexander Zverev.
"This Match in Africa is a dream come true. I will play in my mother’s home country against my toughest rival and friend Rafa Nadal." - Roger Federer
This is the sixth Match For Africa to raise money for the Roger Federer Foundation which helps children in Africa and Switzerland.
The first was also between Federer and Nadal, on 21 December 2010, in Zurich's Hallenstadion.
Two days later, they played a return fundraiser in Madrid for the Fundacion Rafa Nadal which benefits youngsters in Spain and India.
The second Match for Africa was in Zurich four years later with Stan Wawrinka, Federer's gold medal doubles partner from Beijing 2008, the opponent.
At the latter, Federer teamed up with Microsoft founder and philanthropist Bill Gates for a doubles match against Isner and Pearl Jam guitarist Mike McCready.
The occasional doubles partners have become firm friends with Gates writing Federer's Time 100 eulogy in 2018 honouring his sporting achievements and charity work.
San Jose hosted the most recent Match for Africa in March 2018 with Federer taking on Rio 2016 mixed doubles gold medallist Jack Sock after he and Gates faced Sock and NBC Today anchor Savannah Guthrie.
Now the Match for Africa is in Africa for the first time.
While Federer has been a regular visitor to his mother's homeland, this will be the first time he has played in sub-Saharan Africa.
Before the main event, Federer and Gates will go up against Nadal and South African comedian Trevor Noah, the presenter of Comedy Central's The Daily Show.
The last two Matches for Africa raised more than two million US dollars apiece.
With tickets sold out months ago, the hope is that this event will be even more successful.