When Spaniards discovered America they met some rich cultures and very advanced societies but the also found gold and wealth enough to wake up their codice. After some first friendly encounters and the founding of trading posts in the Caribbean and Gulf of Mexico coasts, many Spaniards; Castillian and Andalusian mainly, that had small opportunities in their homeland, begun to move to those trading posts searching better opportunities. The lack of respect of those people for other cultures (mainly non-Christian cultures), the wealth of the Native Americans and the hopelessly existence triggered this people to organize for stealing and killing. Native Americans reacted against Europeans as a whole and the Spanish crown sent regular troops that could content the Native American reaction.
After this happened when most Native American where recovering of the great smallpox outbreak, Spain troops had little resistance in defeating and invading several countries. When Spain attempted to took over the innermost countries, those people had already recovered from the outbreak and had learned, by their fallen neighbors, to fight the Spaniards and their new tactics like gunpowder and riding horses.