Rainn Wilson came to the project via Jenna Fischer's relationship with her ex-husband James Gunn. Gunn was discussing his script with Fischer and asked her to take a look at it, sending her a copy on the set of The Office (2005). Fischer read the script, loved it and thought Wilson would be a great choice as the lead. She gave the script to her co-worker, and Wilson immediately decided to make the film.
Towards the end of the movie when Liv Tyler is in her rehab group session, she is heard stating "f**ked up, insecure, neurotic, and emotional". This is a reference and nod to her rocker father Steven Tyler (of Aerosmith) and his 1980's song "FINE" which is an acronym for the same line.
The role of Jacques was supposed to be played by an unspecified actor up until a week before shooting began. Gunn said "the guy was kind of AWOL. I just couldn't risk that personality type on this movie." Kevin Bacon stepped in as a last minute replacement.
Ellen Page's character Libby ("Boltie") uses metal claws like Wolverine. Page played Kitty Pryde in X-Men: The Last Stand (2006). At one point in the comics, and during the alternate reality of the Age of Apocalypse, Kitty Pryde uses metal claws as part of her costume just as Boltie does.
Towards the end, when his wife is lying in bed, he says something about her needing to have nightmares. As he says this, her fingers makes the classic Spiderman web-slinger motion with the two middle fingers of her hand striking the palm. Possibly a nod to how she needed a hero at the time, and Spidey was in her dream.
At the end of the movie when Sarah (played by Liv Tyler) is at her Narcotics Anonymous meeting, she talks about being "FINE" (F'd up, Insecure, Neurotic and Emotional) which is the title of one of Liv Tyler's dad's songs (F.I.N.E. by Aerosmith).