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The Vikings were the first Europeans to reach the Americas, starting but then abandoning a colonisation process. (For more on this, see Vinland.)

The first phase of modern European activity in this region began with the oceanic crossings of Christopher Columbus (1492-1500), sponsored by Spain, and those of other explorers such as John Cabot, sponsored by England, and Giovanni da Verrazano, sponsored by France and according to some the German Didrik Pining and Polish John of Kolno 1473, sponsored by Denmark.

This was followed, notably in the case of Spain, by a phase of conquest: The Spaniards (just having finished a war against the Muslims in the Iberian peninsula) replaced the Amerindian local oligarchies and impose a new religion: Christianity. European diseases and cruel systems of work (the famous haciendas and mining industry) decimated the Amerindian population. African Negro slaves were introduced to substitute the Amerindian. On the other hand, the Spaniards did not impose their language in the same measure and the Catholic Church even evangelized in Quechua, Nahuatl and Guarani, contributing to the expansion of these Amerindian languages and equipping them with writing systems. One of the first school for Amerindians was founded by Fray Pedro de Gante en 1523.

The Portuguese switched from an initial plan of trading posts to an extensive colonization of what is now Brazil.

(See also: Conquistador, Francisco Vasquez de Coronado, Hernán Cortés, Francisco Pizarro, Spanish Conquest of Yucatan, Treaty of Tordesillas, Treaty of Alcaçovas)

In the British and French regions, the focus of economy soon shifted from resource extraction to trading with the natives. This was also practiced by the Russians in the northwest coast of North America. After the French and Indian War, Great Britain captured all French possessions in North America.

Slavery under European rule began with importation of white European slaves (or indentured servants), was followed by the enslavement of local aborigines in the Caribbean, and eventually was primarily replaced with Africans imported through a large slave trade as the native populations declined through disease. But by the 18th century, the overwhelming number of black slaves was such that white and Native American slavery was less common.