Neither David Cross's nor Jeffrey Tambor's characters were ever intended to be regular characters. It was not until the actors tested well that the writers ended up putting them regularly in the series.
Ron Howard's role as the narrator was accidental. He was merely filling in on the pilot, but his voice just "worked."
Michael Cera, who is Canadian, had problems with his work visa, and was almost unable to complete work on the pilot episode. Cera had to go to Tijuana, Mexico in order to obtain another visa. Michael Angarano was on standby to replace Cera, in case he was deported.
Nearly every episode begins with "Michael" or "Michael Bluth" as the opening word(s).
In "Let 'Em Eat Cake (2004)," Alessandra Torresani played George Michael (Michael Cera)'s girlfriend Ann, and her brief performance was singled out for praise by the rest of the cast on the DVD commentary for the episode. By season two, however, Ann was played by the very different-looking Mae Whitman. This casting change is possibly a joke, since Michael repeatedly forgets what Ann looks like, and Maeby (Alia Shawkat) jealously calls her "No Face." Mae Whitman later clarified that the original plan was for Ann to be played by a different actress every episode, hence the joke that Michael can never remember what she looks like, but joked that the producers thought she was forgettable enough for the joke to work (though it may also have to do with Fox cutting the episode count and the budget for Season 2 after low ratings).