Prior to Columbus's voyages, well-developed trade routes linked the peoples and products of Africa, Asia, and Europe. Overall, Europe played a minor role in the Afroeurasian trade world because it did not produce many products desired by Eastern elites. Nevertheless, Europeans — especially Venetian and Genoese merchants — sought to tap into the goods and wealth of Afroeurasian commerce. As the economy and population recovered from the Black Death, Europeans began to seek more direct and profitable access to the Afroeurasian trade world. Technological developments such as the invention of the caravel and the magnetic compass enabled men like Christopher Columbus and Ferdinand Magellan to undertake ever more ambitious voyages.

In the aftermath of their conquest of the Aztec and Inca Empires, the Spanish established new forms of governance to dominate native peoples and exploit their labor, including the encomienda system. The arrival of Europeans brought enormous population losses to native communities, primarily through the spread of infectious diseases. Disease was one element of the Columbian exchange, a complex transfer of germs, plants, and animals between the Old and New Worlds. Over time, the Columbian exchange brought new crops to both the New and Old Worlds — crops that eventually altered consumption patterns internationally. These exchanges contributed to the creation of the first truly global economy. Tragically, a major component of global trade was the transatlantic slave trade, in which Europeans transported, under horrific conditions, Africans to labor in the sugar plantations and silver mines of the New World. European nations vied for supremacy in global trade, with early Portuguese success in India and Asia being challenged first by the Spanish and then by the Dutch, who took control of trade with the East in the mid-seventeenth century.

Increased contact with the outside world led Europeans to develop new ideas about cultural and racial differences. Debates occurred in Spain and its colonies over the nature of the indigenous peoples of the Americas and how they should be treated. Europeans had long held negative attitudes about Africans; as the slave trade grew, they began to express more rigid notions of racial inequality and to claim that Africans were inherently suited for slavery. Most Europeans, with some important exceptions, shared such views. Religion became another means of cultural contact, as European missionaries aimed to spread Christianity in the New World.