Wales must record consecutive wins over South Africa for the first time if they are to reach the World Cup semi-finals.
Warren Gatland's side face the Springboks on Saturday at Twickenham with just two wins from 30 previous meetings between the countries.
Heyneke Meyer's team lost to Wales last year but will hope their resurgence since the defeat to Japan continues.
Dan Lydiate, Tyler Morgan and Gethin Jenkins return to the Wales side while JP Pietersen is back for South Africa.
Wales have a poor record overall against the southern hemisphere sides, with last Saturday's 15-6 loss to Australia their 11th consecutive defeat against the Wallabies while they have not beaten New Zealand since 1953.
Wales relishing knock-out phase
Coach Gatland is not concerned by Wales' poor record against the 'Big Three' and expects his side to revel in the knock-out atmosphere of the World Cup.
Gatland's side are seeking to set up a last-four tie with either New Zealand or France.
"I think if you get to this stage you have to back yourself, don't you?" he said.
Gatland's views were echoed by his captain Sam Warburton, who is viewing the game as an opportunity to inflict a significant defeat on one of the southern hemisphere giants.
"Players never talk about history or psychological battles. I think that's irrelevant," said the 2013 Lions captain.
"It doesn't matter who you are playing or what record you've got, there's always a chance of winning, otherwise no one would watch.
"It's a target of mine to have a World Cup when we beat a southern hemisphere team when it matters. That's quite important to me."
Tough route has helped Springboks
Springboks coach Meyer admits his side have had a harder route to the quarter-finals than they had hoped for following the opening-game defeat against Japan.
"It's been tough, look at my grey hair," he said.
"It's hard when you have to win every single game, but it has helped us.
"You always have to look at your opponents and respect them. They have also been under huge pressure in their pool, so it's probably the same for both teams.
"But we've got all the players back that we wanted right from the start and they are hitting form. We're playing knock-out rugby and hopefully we can take that further."
Team news
Wales blind-side flanker Dan Lydiate returns with a plate inserted to repair the eye socket injury which kept him out of the 15-6 defeat against Australia.
The other two changes from that side see 20-year-old Tyler Morgan come in at centre with George North returning to the wing in place of the injured Liam Williams.
Loose-head prop Gethin Jenkins takes over from Paul James in the front row while lock Alun Wyn Jones makes his 100th Test match appearance - 94 for Wales to add to six Lions Tests.
After the shock 34-32 defeat to Japan in their opening pool game, Springboks coach Meyer has fielded a relatively settled line-up.
The return of wing JP Pietersen is the only change from the starting XV that beat USA 64-0 in their final pool game.
Victor Matfield's continuing injury problems mean another run-out for the youthful second-row pairing of Lood de Jager and Eben Etzebeth.
Key players
Alun Wyn Jonescis making his 100th Test match appearance and has been described by Gatland as "immense for us".
"He's such a competitor and wants to win desperately. He understands and believes he can compete with the best in the world and he's had an unbelievable World Cup."
Fourie du Preez the scrum-half and captain doubted his ability to take part in the tournament after a series of injuries, but Meyer was determined to persuade him to travel.
"I was on my knees and asked him just to train with the side," said the Springboks coach.
"If you have him in your side and he clicks, he is as valuable as Richie McCaw is to the All Blacks."
South Africa's team boasts five players who have played in and won a World Cup final. Bryan Habana, Schalk Burger, Fourie du Preez and JP Pietersen all started in the 15-6 win over England in the 2007 final. Bismarck du Plessis came on for five minutes as a blood replacement in the second half while his brother Jannie was on the bench but did not play.
Wales have only ever beaten the Springboks twice - in 1999 and the last meeting between the teams in November 2014. There was a 6-6 draw in 1970 and Wales suffered their heaviest international defeat against them - the 96-13 mauling in Pretoria in June 1998.
Wing Habana is on the brink of two try-scoring landmarks. He needs one to become the leading try scorer on his own in the World Cup - he is currently tied on 15 with New Zealand's Jonah Lomu. A try against Wales would also take him past David Campese in Test rugby's all-time try-scoring list. They both have 64 tries - five behind Japan's record-holder Daisuke Ohata.
Wales: Gareth Anscombe; Alex Cuthbert, Tyler Morgan, Jamie Roberts, George North; Dan Biggar, Gareth Davies; Gethin Jenkins, Scott Baldwin, Samson Lee; Luke Charteris, Alun Wyn Jones; Dan Lydiate, Sam Warburton (capt), Taulupe Faletau.
Replacements: Ken Owens, Paul James, Tomas Francis, Bradley Davies, Justin Tipuric, Lloyd Williams, Rhys Priestland, James Hook.
South Africa: Willie le Roux; JP Pietersen, Jesse Kriel, Damien de Allende, Bryan Habana; Handre Pollard, Fourie du Preez (capt); Tendai Mtawarira, Bismarck du Plessis, Frans Malherbe; Lodewyk de Jager, Eben Etzebeth; Schalk Burger, Duane Vermeulen, Francois Louw.
Replacements: Adriaan Strauss, Trevor Nyakane, Jannie du Plessis, Pieter-Steph du Toit, Willem Alberts, Ruan Pienaar, Pat Lambie, Jan Serfontein.
