Chapter 4 of 1491 describes the rise and fall of the Aztec Empire through the story of the Mexica people and its leaders. The main argument of this chapter addresses concerns raised in the previous chapters regarding the lethality of epidemics in the Americas, and their effect on indigenous peoples.

Chapter 4 begins with a discussion of a "vulnerability" hypothesis for the indigenous peoples of the Americas. The hypothesis suggests that the certain patterns of genetic homogeneity predisposed native peoples to be particularly susceptible to infection and death from smallpox and other diseases. This, combined with the movement of peoples, along with Europeans' close contact with animals, amplified the effects of disease. One important outcome of this discussion is the attempt to determine simply how many people lived on the continents, prior to the arrival of Europeans. Though conquistadors and travelers describe vast, densely-populated metropolises in their journals, most of these urban centers disappear or have much smaller overall populations by the latter half of the 16th century. Tenochtitlan, the capital of the Aztec Empire, is an exception—it is larger than any European city at the time. To conquer Tenochtitlan, Hernán Cortés musters an army of reportedly 200,000 people.