Bolton Wanderers knocked holders Arsenal out of the FA Cup on Saturday, Greek striker Stelios Giannakopoulos heading an 84th-minute goal to earn a 1-0 fourth-round victory at the Reebok Stadium.
Premier League leaders Chelsea needed a second-half fightback to draw 1-1 at Everton while third division Brentford pulled off the shock of the day by beating top-flight Sunderland 2-1.
Middlesbrough and Birmingham City face replays after being held to 1-1 draws by second division opposition, Coventry City and Reading respectively.
Third division Leyton Orient suffered a last-gasp 2-1 defeat at London rivals Charlton Athletic.
West Ham United beat Blackburn Rovers 4-2 and Manchester City overcame Wigan Athletic 1-0 in two all-Premier League games while there was an upset win for third division Colchester United, who ousted second division Derby County 3-1.
Last season's runners-up Manchester United visit Wolverhampton Wanderers on Sunday when European champions Liverpool are also in action at Portsmouth.
Arsenal suffered their second surprise cup exit in four days following their League Cup semi-final defeat by Wigan on Tuesday.
Manager Arsene Wenger paid the price for fielding an inexperienced team against Bolton, a side who have made a habit of upsetting his side.
Arsenal hit the bar through Robin van Persie and Sol Campbell but were left stunned when Jamaican midfielder Ricardo Gardner curled a perfect cross on to the head of a diving Giannakopoulos, who also scored in Bolton's 2-0 league win over the Londoners in December.
"It shows our improvement," Bolton manager Sam Allardyce told Sky Sports.
"When they go out and play at the Reebok Stadium the lads fear nobody, they feel like they can beat anybody."
Everton have also proved awkward opponents for Chelsea in recent seasons and took the lead in the 36th minute when James McFadden rose to head home a superb cross from Nuno Valente.
Chelsea were transformed after the break and got a deserved equaliser in the 73rd minute when England midfielder Frank Lampard surged on to a William Gallas cross to shoot home.
"I think it's a good result," Chelsea manager Jose Mourinho told the BBC.
"It will be much more difficult for them (at Stamford Bridge) than at Goodison Park. It's a different kind of match for us and them and I think we can do it."
Brentford missed a series of chances against Sunderland, eight points adrift at the bottom of the Premier League, before Dudley Campbell kept his cool to put them ahead after 57 minutes.
Julio Arca equalised but Brentford, fifth in the third division, won it a minute from time with Campbell's superb second to spark an old-style, good-natured pitch invasion at the dilapidated west London ground.
Brentford manager Martin Allen said he would be celebrating in unorthodox style.
"It won't be probably until I get away from here...and I sit in my car on my own, just have a smile and look out the window," he told the BBC.
The defeat was another nail in the coffin of Sunderland manager Mick McCarthy.
Newcastle United boss Graeme Souness lived to fight another day after his troubled side won 2-0 at fourth division Cheltenham Town.
Souness has been under mounting pressure and Newcastle were again below par on Saturday, winning with fortunate goals by Michael Chopra and Scott Parker late in the first half.
Reading are on course for promotion to the Premier League for the first time and, even after resting several first team regulars, were a match for Birmingham, who could well swap places with them in May.
Teenage striker Shane Long shot Reading ahead in the 31st minute before Birmingham, who beat Portsmouth 5-0 in their previous match, levelled through David Dunn after 67.
Orient, who knocked out Fulham in the third round, looked on course for another good day against another Premier League London rival until Jay Bothroyd won it for Charlton in the last minute.