Everton and Tottenham scored nine goals between them on their travels as they defeated Hull and Preston respectively. Everton cruised to an emphatic 4-0 defeat of under-strength Hull and found themselves three goals to the good after only 24 minutes.
A fourth was added early in the second period as David Moyes' men begin to find their form.
Tottenham made seven changes, travelled to Preston and hammered the Championship outfit 5-1, including a hat trick from Peter Crouch.
Chelsea midfielder Joe Cole returned from his long-term knee injury and set up the only goal of the game by Salomon Kalou in the 1-0 defeat of QPR at Stamford Bridge.
Gabriel Agbonlahor's third minute strike was enough to overcome Cardiff 1-0 at Villa Park. Villa had crashed out of the competition to lower-league opposition in three of the previous four seasons.
Manchester United survived the sending off of Fabio at Old Trafford to progress at the expense of Wolves by a second half Danny Welbeck goal.
The visitor's had their chances but United held firm.
Manchester City meanwhile needed extra time to get past an under strength Fulham.
City dominated for most of the game but fell behind to Zoltan Gera only for Gareth Barry to level.
Fulham clung on until extra time when Kolo Toure headed in the winner from a corner.