1500-1549
- 1512: Spanish Laws of Burgos forbid enslavement of Indians and advocate Christian conversion.
- 1514: Bartolome de las Casas petitions Spanish crown on behalf of Native Americans
- 1519-1521 Cortes's conquest of Aztecs in Mexico.
- 1528-1536 A member of the Narvaez expedition, Alvar Nunez Cabeza de Vaca is shipwrecked first near Tampa Bay and later on Galveston Island off the coast of what is now Texas. After six years spent among the Indians of the region, he and his companions travel westward across Texas and Mexico.
- 1540-1542 Seeking gold first in the city of Cibola, reportedly larger and richer than Mexico City, and then in Quivera, Francisco Vasquez de Coronado leads an expeditionary force through the Texas and Oklahoma panhandles, with much loss of life among the area's native peoples. He returns to Mexico City in 1542 and dies in 1544.
- 1542 Urged on by Bartolome de las Casas and others, Carlos V enacts the "New Laws" designed to end the encomienda system that enslaves native people.
