The GEICO gecko was voiced by Kelsey Grammer in his first ad, then Dave Kelly, and finally Jake Wood. The first one may be a different character; he doesn't work for the company, he just wants Geico customers to stop calling him by mistake.
Speedy from the Alka Seltzer commercials was originally voiced by veteran voice actor Dick Beals. When he was revived decades later, he has since been voiced by Debi Derryberry.
The baby in the E-Trade commercials has changed several times over the years for obvious reasons.
Altel's commercials featuring a group of nerds working for different cell-phone companies changed the actor playing the Sprint guy, notable because he later donned a previously absent afro.
Chicago area car dealership O'Conner Ford went through several spokewomen, all of whom were (allegedly) his daughter Katie.
Another Chicago auto dealer, Howard Pontiac, went through two spokesmothers.
In a The Flintstones commercial for Busch Beer from 1967 most of the cast were able to reprise their roles with the sole exception of Jean Vander Pyl as Wilma Flintstone, for some reason she was unable to voice her so they had Betty's voice actress Gerry Johnson voice her instead.