- Acting for Two: Jeremy Piven portrays both Tick Tock and the Time Keeper / Danger D'Amo. In the Latin dub, Pedro D'Aguillón Jr. also played said characters altogether.
- Contractual Obligation Project: Robert Rodriguez didn't want to make another one and was in no hurry to make another film for producer Harvey Weinstein after he was single-handedly blamed for the failure of Grindhouse. However, he owed Weinstein one more movie in a contract signed before that movie was released and Weinstein wanted a sequel. This was the result.
- Deleted Role: Antonio Banderas' scenes were cut from the film.
- Inspiration for the Work: The genesis for this film came from an incident on the set of Machete. Jessica Alba had her then-one year old baby Honor Marie and was dressed to appear on camera when her diaper "exploded". Watching Alba change the diaper while trying not to get anything on her clothes prompted Robert Rodriguez to think "What about a spy mom?"
- The Other Darrin: Raúl Garduño dubbed Juni Cortez in the first three films. However, he retired in 2005, so in this film he was replaced by Víctor Ugarte.
- Real-Life Relative: Víctor Ugarte and Gaby Ugarte, who played Juni and Carmen in the film's Mexican dub, are actually siblings in real life.
- Sequel Gap: The film came out eight years after Game Over.
- So My Kids Can Watch: Why Jessica Alba and Joel McHale starred in the film.
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