For Michael Chiklis' performance as the Thing, a new set of prosthetics were developed. These prosthetics were easier for Chiklis to wear, as they provided better ventilation and could be easily removed, in comparison to the previous film's prosthetics which required six hours to apply, were uncomfortable and could not be easily removed.
Jessica Alba, upon receiving criticism about her performance in this film, said that the director, Tim Story, told her "It looks too real. It looks too painful. Can you be prettier when you cry? Cry pretty, Jessica... Don't do that thing with your face. Just make it flat. We can CGI the tears in."
Jessica Alba wore a blonde wig because her hair had suffered from all the bleaching in Fantastic Four (2005).
The studio hated Doctor Doom's make-up so he remains hidden under a cowl in most of his early scenes.
Originally, Laurence Fishburne was keen to provide the voice for Galactus. He happily switched to the role of the Silver Surfer when it was decided to make Galactus mute.
Stan Lee: (at around 19 mins) as a guest who is refused entry to the Fantastic wedding. This is taken from an issue of the 1960s "Fantastic Four" comic, where at Reed Richards and Susan Storm's wedding, Stan Lee and series artist Jack Kirby are turned away from the wedding, in a blatant breaking of the fourth wall, which was very rare in the mainstream Marvel Comics universe.