This is the sequel to 1995's Loaded, with an improved graphics engine, and just as much violence and blood. Re-Loaded puts you in the shoes of a number of characters, each weird, deformed, and generally strange. It is a mission based game, where you must complete various objectives to successfully win in each of the 12 worlds. Throughout each mission, you must kill lots of people, with a variety of weapons such as plasma cannons, lasers and ultra bombs.

F.U.B., the antagonist of Loaded, had his body destroyed at the end of the previous game, although his brain fled in an escape pod. Landing on a harsh desert world, Kee-Butt-5, his brain has been implanted into the body of a chiselled, bronzed young artist hermit named Manuel Auto, and then he murdered the loyal surgeons responsible for giving him a new body. Reincarnated and renamed "C.H.E.B.", which stands for "Charming Handsome Erudite Bastard", the former raving lunatic supervillain has taken on some of the aspects of his host body, the creative, artistic and thoughtful Manuel Auto. With his matter manipulation powers, C.H.E.B. plans to transform whole planets into "Works Of Art and Genius", starting with his own body which he grows to the size of a small moon. Once again the group of blood-thirsty anti-heroes gather to bring him down once and for all and set off for Kee-Butt-5...