England trail by 269 after closing the third day against South Africa at Headingley on 50-2 in their second innings.
South Africa batted until after tea to extend their first innings to 522 all out, a lead of 319, mainly thanks to AB de Villiers' innings of 174.
And the day improved further for the Proteas with the wickets of Andrew Strauss and Michael Vaughan to leave England facing defeat.
Makhaya Ntini had both caught behind, Strauss in the fourth over for a 13-ball duck and Vaughan (21) nine deliveries before the close to end a promising 47-run stand with Alastair Cook (23no).
Ntini (2-16) was unfortunate not to add James Anderson to his list of victims, the nightwatchman padded up in front of middle stump to his second ball, but umpire Billy Bowden declined South Africa's vociferous lbw appeal.
But with six sessions still remaining and the weather forecast set fair, England's hopes of escaping Leeds with a draw appear bleak.
The tourists began the third day at 322-4 in their first innings and pursued a policy of steady accumulation during the first two sessions.
They added 62 runs in the morning for the loss of just Ashwell Prince, although by the time Darren Pattinson induced an edge behind, Prince had already surpassed his previous best score in Tests.
The left-hander, who also scored a century in the first Test, added 15 to his overnight position of 134 before Pattinson (2-95) got a delivery from around-the-wicket to hold its line just enough.
That was the hosts' first success for 75 overs and ended a South African record fifth-wicket stand of 212 against England.
De Villiers endured a lengthy wait on 99 before stealing a single to mid-on to reach his sixth Test century just before lunch, the Headingley crowd gave the landmark a mixed reception following his controversial catch-that-wasn't on the first day.
The 24-year-old was far from finished, going on to up the tempo during an afternoon session that saw 96 runs added.
England did manage to remove Mark Boucher (34), via a bottom-edged pull into his stumps off Anderson (3-136), and Morne Morkel (0), bowled between bat-and-pad aiming a drive at a flighted Monty Panesar delivery.
Vaughan took the third new ball in an effort to end an 84-run, eighth-wicket alliance between de Villiers and Paul Harris that took South Africa's innings past 500 and their lead beyond 300.
De Villiers' 381-ball, eight-and-half hour knock was finally ended on 174 by a flashing drive at Stuart Broad (1-114), the resulting edge brilliantly taken, low down in his left hand by Andrew Flintoff at slip.
Panesar polished off the innings by removing Harris (24) and last man Ntini (1) via ambitious aerial blows to finish with respectable figures of 3-65.
