According to Atsushi Inaba, he and his team were fans of Frank Miller's Sin City, inspiring the artistic direction for the game's graphics.
The bosses in Area 66, The Masters, are loosely based on Obi-Wan Kenobi and Anakin Skywalker from the Star Wars franchise.
The finisher for the 2nd boss, Jude the Dude, was originally going to be different. In the original, Jack would take Jude's revolvers and shove them into Jude's anus. Jack then shoves them deeper and pulls the trigger, sending Jude flying and exploding into a shower of blood.