The Age of Exploration
Speaking of Spanish conquests, the age great of explorers is the perfect untapped setting for a game. Pioneers like Sir Frances Drake (ancestor of our favorite modern day treasure hunter, Nathan Drake), Hernan Cortes and Christopher Columbus pushed violently Westward, all in the name of progress, mowing over entire civilizations with wanton disregard for any culture but their own.
It was all epically tragic, and witnessing the "discovery" of America, the downfall of the Aztec Empire and the corruption of spice trade monopolies in a high-production game would be beyond cool.
Naughty Dog could easily go mega-retro with the Uncharted series, providing some context for all the cryptic maps and dusty journals Nate Drake is always sticking his nose in. Throw in some old school nautical gameplay and we're sold.
If you've got a better idea than the ones we've mentioned (and we're sure you do), go ahead and let us know in the comments or on Twitter!