By 1560, the major centers of Indian civilization had been conquered, their leaders overthrown, their religion held in contempt, and their people forced to work for the Spaniards. Profound demoralization pervaded Indian society.

Adding to the culture shock of conquest and colonization was the deadly toll of European diseases. As conquest spread, the Indians succumbed to epidemics of measles, smallpox, and respiratory illnesses. They had no immunity to these diseases because they had not been exposed to them before the arrival of Europeans. By 1570, the Indian population of New Spain had fallen about 90 percent from what it was when Columbus arrived, a catastrophe unequaled in human history.

For the Spaniards, Indian deaths meant that the most valuable resource of New Spain — Indian labor — dwindled rapidly. By the last quarter of the sixteenth century, Spanish colonists began to import African slaves. In the years before 1550, while Indian labor was still adequate, only 15,000 slaves were imported from Africa. The relatively high cost of African slaves kept imports low, totaling approximately 36,000 from 1550 to the end of the century. During the sixteenth century, New Spain continued to rely primarily on a shrinking number of Indians.