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".
For Michael Chiklis's 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.
Originally, Nick Fury was going to be in this film, but he was written out of the script and replaced with General Hager. Fury would eventually appear in the Marvel Cinematic Universe opposite Chris Evans who played Steve Rogers/Captain America.
In the comics, Doctor Doom constantly wears his trademark suit of armor since an accident in his laboratory. There is a tradition of never showing his face under the mask (by having some object come into the panel to obscure his front whenever he takes it off) with the understanding that there is nothing beneath but scar tissue.
For this outing, some slight revisions were made to the make-up of The Thing, giving him a larger brow and broader shoulders. This brought the design more in line with the then-recent comic book revision.
There is a dialogue in the movie when Reed says that he is engaged to the hottest woman on the planet (pointing to Susan Storm). This was a reference to the fact that Jessica Alba had been declared the sexiest female alive just months before the release of this film.
Stan Lee: 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.
The trivia items below may give away important plot points.
In the film, the Silver Surfer gets his powers from his board, which was not the case in the comics. In the comics, the Surfer is able to fly on his own and use his full gamut of powers without the aid of his surfboard. The board's purpose is that it significantly decreases the energy required for flight.
In the original script, it was Reed's idea to have Johnny assume all the team's powers to fight Dr. Doom, and Johnny had to be talked into it. Tim Story later made it Johnny's idea, to make the scene Johnny's big moment and give Chris Evans a chance to really shine.
According to Don Payne, the film was influenced by the Fantastic Four comic "The Galactus Trilogy" (Galactus and the Surfer approach Earth), "Fantastic 4" issues #57-60" (Dr Doom steals the Surfer's powers), and the "Ultimate Marvel" comic "Ultimate Extinction" (the name of Gah Lak Tus is used).
Tim Story refuses to put giant robots in his movies. In this film, Galactus, normally portrayed in the comics as something resembling a giant robot, is shown as a gaseous cloud. However, both the shadow on Saturn as he passes by it and the fiery mass within the cloud, resemble his signature helmet.
The Human Torch gains all of the Fantastic Four's powers in the final battle against Doom. This is a direct reference Fantastic Four villain Kl'rt aka Super Skrull who possesses a conbination of all of the Fantastic Four's powers.
Tim Story wanted the Four's iconic laying-on of hands to serve a practical purpose in the film, not to be just a go-team gesture. Hence its use when Johnny assumes all of the team's powers in order to fight Dr. Doom and the Surfer's board.