The early sixteenth century marked the end of independent empires of the Americas and the gradual integration of American peoples into global empires seated in Europe. Spaniards were the most motivated and had their greatest success when they encountered dense, organized urban areas. Here they displaced existing overlords as the recipients of tribute in goods and labor. The Spanish were less interested in sparsely settled areas that did not have well-established systems of trade and tribute and were harder to subdue. As a result, European conquest was a surprisingly drawn-out process. Peoples of the Americas resisted conquest until well into the nineteenth century.

The incidental companion of conquest — disease — was also uneven in its effects. Over the course of the sixteenth century, epidemic diseases decimated the population of the Americas, which fell from 50 million to just 5 million. But epidemics of diseases that are spread through human contact, such as measles and smallpox, are primarily urban phenomena: these diseases emerged as ancient cities grew large enough that the diseases could spread quickly among dense populations. As a result, the impact of the diseases brought by Europeans was the most severe and the most destructive in the cities of the Americas.

Since cities faced the brunt of both disease and wars of conquest, the disruptions caused by the encounter were disproportionally felt there. Whole systems of knowledge, sets of artisanal skills, political cultures, and religious thought resided in cities. Thus, as epidemics erupted, many of the most remarkable aspects of American civilizations were lost. Rural peoples and cultures were much more resilient. It was in rural areas that languages, foodways, farming practices, and approaches to healing — indeed whole worldviews — endured and evolved. This process occurred either in isolation from or in dialogue with European cultures, but local practices in rural regions were not obliterated, as they were in major cities. In the end, the European encounter destroyed the urban cultures and systems of knowledge in the Americas.