We analyzed the various factors that led to the Age of European Exploration and Discovery at the end of the fifteenth century. Specifically, we examined the economic opportunity that arose following the Fall of Constantinople in 1453, the various technological advances making long-distance sea travel possible(e.g.,invention of the caravel, lateen sail and dry compass),the rise of nationalism in Europe resulting from the disintegration of the feudal system, the enhanced zeal to spread Christianity resulting from the expulsion of the Moors from the Iberian Peninsula, and the impact of the Renaissance in stimulating scientific/intellectual curiosity. We also discussed briefly some of the factors as to why Native Americans were especially vulnerable to European discovery at this particular time and the three major factors that led to the decline of Spanish military, economic and political power at th end of the sixteenth century.