Third-tier Oldham Athletic have stunned seven-time FA Cup winners Liverpool with a shock 3-2 fourth-round win and Leeds United have caused another big upset by knocking out Tottenham Hotspur 2-1 at Elland Road.
Holders Chelsea were also heading for a surprise defeat at third-tier Brentford until Fernando Torres hit a late equaliser to salvage a 2-2 draw.
Defeat for Liverpool and Spurs took the number of Premier League casualties losing to lower division opponents in the last 32 to five following defeats for Norwich City, Queens Park Rangers and Aston Villa.
Oldham, languishing in 19th place in League One, were irresistible in front of their own fans at Boundary Park, going ahead with a Matt Smith header in the second minute.
Luis Suarez levelled but Smith's second and a third goal from Reece Wabara made it 3-1 after 48 minutes.
Joe Allen's deflected volley with 10 minutes left gave Liverpool hope but, despite relentless pressure, they could not find another with Steven Gerrard rattling the crossbar from long range.
Goals from Luke Varney and Ross McCormack put second-tier Leeds, Cup winners in 1972, in control against Spurs with Clint Dempsey's header not enough to save the Londoners.
Much-maligned Spanish striker Torres swept home on 83 minutes to secure a replay for Chelsea at Stamford Bridge.
Having missed out on one Wembley appearance after losing over two legs to Swansea City in the Capital One (League) Cup semi-finals, Chelsea twice needed to come from behind at Griffin Park.
After becoming the first Champions League holders to exit at the group stage and 11 points off top spot in the Premier League, Chelsea's path to silverware this season rests with the Europa League or with the FA Cup, a trophy they have lifted in four of the last six seasons.
Trailing 2-1 when Harry Forrester slotted in from the penalty spot with 17 minutes left, Torres, a pale shadow of the striker that Chelsea paid a British transfer record fee of 50 million pounds ($79 million) for in 2011, kept the Cup holders in the competition.
He took a pass from substitute Demba Ba and beat goalkeeper Simon Moore with a precise finish.
"I was pleased with the reaction of the players, we were much better in the second half," Chelsea interim manager Rafael Benitez told reporters.
"We knew what Brentford were capable of and they did it well, so credit to them, but we need to do our job in the replay."
Brentford, pushing for promotion to the second tier of English football and managed by former Manchester City striker Uwe Rosler, had harried their more illustrious London rivals and denied them space for much of an enthralling game.
Sharper to the ball in the opening period, they led late in the first half when Chelsea keeper Ross Turnbull, deputising for Petr Cech who was rested with a niggle, could only parry a shot into the path of Marcello Trotta and the on-loan Italian striker lashed in.
Chelsea were vastly improved after the break and equalised on 55 minutes when a clearance fell to Oscar on the edge of the box and with his back to goal, the Brazilian turned and found space inside the area to prod a right foot shot home.
The Premier League side were on top at this stage but Brentford did not buckle and appeared to be on their way to one of the biggest ever shocks in the competition when Turnbull sent Tom Adeyemi sprawling in the penalty area.
Forrester coolly slotted in the spot kick to give Brentford a 2-1 lead but Torres, inconsistent and forlorn for much of the season, was to have the final word.
