Firebrand fast bowler Kagiso Rabada bagged two wickets as South Africa reduced England to 52 for three at the close of day four of the final Test on Monday.
The tourists, who have already won the series, need a further 330 for what would be a record-breaking victory on the final day but must do so on a wicket showing variable bounce and prodigious turn at CenturionPark.
England's hopes of an unlikely victory or survival will rest on Joe Root (19 not out) who is at the crease with James Taylor (19 not out) after Rabada gave the hosts the perfect start.
The 20-year-old forced another failure from opener Alex Hales who was trapped lbw for one by a ball that kept low and jagged into him.
Rabada claimed his ninth wicket of the match when he had Nick Compton (six) caught behind, the England batsman unsuccessfully reviewing what seemed an obvious edge.
With a tense final day likely, England will hope that wasted review does not come back to haunt them.
In between, Morne Morkel grabbed the prize scalp of England captain Alastair Cook (five) with a brilliant one-handed caught and bowled to leave the latter still 36 runs short of 10,000 Test runs after a poor series.
South Africa should have celebrated the wicket of Root as well, but wicketkeeper Quinton de Kock failed to take the ball after spinner Dane Piedt had drawn the batsman from his crease and beaten the edge.
South Africa earlier declared their second innings on 248 for five.
Hashim Amla fell four short of a second century in the match when he uncharacteristically flashed wildly at a wide deliver from Stuart Broad in the pursuit of quick runs.
Amla added 117 for the fifth wicket with Temba Bavuma (78 not out), who showed great application and maturity.
The highest successful chase in Test matches at Centurion Park is 251 by England in 2000, though the pitch was only used for two days in that match after rain spoiled the conTest and the teams decided to forfeit an innings each to force a result.
Thunderstorms are forecast in Pretoria on Tuesday, though those will likely come late in the afternoon.