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Post-contact, 1492–1910

During the so-called Age of Discovery, Europeans explored overseas and staked claims to various parts of North America, much of which was already settled by indigenous peoples. Upon Europeans' arrival in the " New World ", indigenous peoples had a variety of reactions, including curiosity, trading, cooperation, resignation, and resistance. The indigenous population declined substantially following European arrival, primarily due to the introduction of Eurasian diseases, such as smallpox, to which the indigenous peoples lacked immunity, and because of violent conflicts with Europeans. Indigenous culture changed significantly and their affiliation with political and cultural groups also changed. Several linguistic groups died out, and others changed quite quickly.

On the North America's southeastern coast, Spanish explorer Juan Ponce de León, who had accompanied Columbus's second voyage, visited and named in 1513 La Florida. As the colonial period unfolded, Spain, England, and France appropriated and claimed extensive territories in North America eastern and southern coastlines. Spain established permanent settlements on the Caribbean islands of Hispaniola and Cuba in the 1490s, building cities, putting the resident indigenous populations to work, raising crops for Spanish settlers and panning gold to enrich the Spaniards. Much of the indigenous population died due to disease and overwork, spurring the Spaniards on to claim new lands and peoples. An expedition under the command of Spanish settler, Hernán Cortés, sailed westward in 1519 to what turned out to be the mainland in Mexico. With local indigenous allies, the Spanish conquered the Aztec empire in central Mexico in 1521. Spain then established permanent cities in Mexico, Central America, and Spanish South America in the sixteenth century. Once Spaniards conquered the high civilization of the Aztecs and Incas, the Caribbean was a backwater of the Spanish empire.

Other European powers began to intrude on areas claimed by Spain, including the Caribbean islands. France took the western half of Hispaniola and developed Saint-Domingue as a cane sugar producing colony worked by black slave labor. Britain took Barbados and Jamaica, and the Dutch and Danes took islands previously claimed by Spain. Britain did not begin settling on the North American mainland until a hundred years after the first Spanish settlements, since it sought first to control nearby Ireland.