The Incas had consolidated their empire only a century before Pizarro and his Spanish conquistadores took control of Inca lands in the 1530s. The Incan heartland was the Andes Mountains from Ecuador down through Peru into parts of northern Chile, including what is now Bolivia, some of Argentina, and in the north, bits of what is now Colombia. It covered about 770,000 square miles, far larger than Spain, and held an estimated 14 million people, more than in Spain, comprised of many different indigenous groups.

Lima was the seat of the Viceroyalty of Peru, which included almost all of the Spanish colonial region in South America. Then, Peru meant today's Peru, Ecuador, and parts of Chile, and in the mid-18th century, a new Viceroyalty of La Plata was set up, based in what is now Buenos Aires. Upper Peru was centered on La Paz and Chuquisaca (since renamed Sucre after the hero of independence), and Peru was centered on Lima and Cuzco. The addition of La Plata as a viceroyalty refocused the necessary slow of silver from Lima and Peru to Buenos Aires and the Atlantic. The Audiencia of Charcas (Bolivia) was placed under La Plata's authority.

In one sense, the Spanish conquest was simply a shift of empires for the indigenous peoples. The Incas were as imperialistic as Spain, and they put down rebellions with the same ferocity. However, Incan rule was generally mild and concerned with the welfare of the empire's people. The indigenous people chafed under Spanish rule, and the lost Incan days were idolized in popular memory. This set the stage for one of the most famous and mythologized conflicts in the history of the Americas.