in D&D if it was set before the Age of Steel? It seems to me that the game has suffered by cleaving unto a late-medieval/early Ren faire setting for so long. Wizards seems to want to push the tech forward, considering Eberron's robots and locomotives. But I think a lot could be gained by turning the primitive savagery to eleven. Like perhaps a game set in stone-age Sumeria or elsewhere in the Middle East of the Old Testament. Greek Age of Heroes, anyone? Bueller? Or maybe a game set in a different culture like that of Nyambe's pseudo-Africa or some sort of Vedic India type thing or maybe Aztecs & Axes. There's been at least one Dragon article (from the 1st edition era) on D&D during the last Ice Age. A dinosaur game with Sleestak's would also rock out. The Polyhedron mini-games like Omega World and Iron Lords of Jupiter also have their appeal. D&D these days just might work for a Thundarr the Barbarian style post-apocalyptic adventure.
I don't think most of these ideas could sustain a lengthy campaign, but Nyambe's got some two ro three available modules. The rest might work on a one-shot basis, like at a con. About a decade ago I ran a 2nd edition AD&D game set in Bronze Age mythic Greece. That turned out fairly successfully. Maybe I should redo that project for 3.5 and run it again. Making semi-divine hero-kings should be much easier under the new rules.
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