Salomon Kalou scored at the start of the second half to clinch Chelsea's 1-0 win over west London neighbor Queens Park Rangers, while Peter Crouch scored a hat trick as Tottenham routed Preston 5-1.
Defending champion Manchester United played for an hour with 10 men and still beat Premier League rival Wolverhampton 1-0 after Danny Welbeck's second-half strike.
At Stamford Bridge, Chelsea's 23rd consecutive unbeaten match equaled a club record as Joe Cole captained the side on his return from nine months out with a knee injury.
The England midfielder could have scored late but struck straight at QPR goalkeeper Tom Heaton. Chelsea was already leading after Cole had slipped the ball through to Kalou in the 52nd minute and the Ivory Coast forward cut inside Mikele Leigertwood on the left clipped in off the post. Yuri Zhirkov, who arrived injured from CSKA Moscow in the offseason, made his debut.
Tottenham, which beat Chelsea in the 2008 final and reached Wembley Stadium again last season, comfortably dispatched Preston.
Crouch volleyed home Gareth Bale's cross for a 14th-minute opener and Defoe headed in a second in the 37th after Preston goalkeeper Andy Lonergan saved his initial shot.
Crouch found the target again in the 77th after connecting with Aaron Lennon's cross. Chris Brown pulled one back for Preston soon after, but Tom Huddlestone surged forward to set up Robbie Keane's goal and Crouch back-heeled in a fifth.
It was a rare night in Manchester with both United and City playing at home.
United, which beat Tottenham in the March final, had Fabio Da Silva sent off on the half hour when the Brazilian defender bundled over Michael Kightly.
From the resulting free kick, former United midfielder David Jones drew a strong save from Tomasz Kuszczak, who replaced Ben Foster in goal. Welbeck broke the deadlock in the 66th, finishing off a flowing move and tucking his shot comfortably past Marcus Hahnemann.
Despite facing a second-string Fulham, Manchester City manager Mark Hughes named a strong lineup, with just one change from the team that lost 4-3 to United on Sunday.
But Zoltan Gera put Fulham in control of the third-round match in the 34th, picking up a loose ball 30 meters (yards) out and hammering a half-volley beyond goalkeeper Shay Given.
City levelled after the break when Gareth Barry headed in Craig Bellamy's corner to send the match into extra time.
Everton raced into a 3-0 lead inside 24 minutes at Hull with Ayegbeni Yakubu, making his first start since last November, Jo and Dan Gosling all finding the net. Leon Osman tapped in a fourth from close range in the 57th.
Aston Villa secured its progression past Cardiff after just three minutes when Gabriel Agbonlahor scored for a fourth successive match.
