From Destroy All Humans! 2 onward due to the usage of non-American characters. Justified as most of the actors being American.
Fake Brit: Actually averted and played straight with Albion NPC characters in Destroy All Humans! 2. While Edita Brychta and Robin Atkin Downes are British actors themselves, every other actor are all American.
While the first game did get a (heavily edited) Japan release, none of the later games in the series were released there.
There is a Playstation 3 Version of "Path of the Furon", but it was released for PAL regions only.
The Other Darrin: A pay dispute caused J. Grant Albrecht and Richard Horvitz (the voice actors of the two lead characters) not to voice their respective characters during Big Willy Unleashed, with Darryl Kurylo and Sean Donnellan replacing them as the voices. Thankfully, however, Albrecht and Horvitz returned in Path of the Furon.
What Could Have Been: In 2006, a TV sitcom produced by the producer of King of the Hill and based on this game was planned. It was scrapped soon after the production of the second game. Oh the possibilities...