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The founding of San Antonio began as part of the Spanish Crown's efforts to populate the vast Texas expanse and to establish its military extension of a settlement frontier. Native Americans first lived along the San Antonio River, calling the area “Yanaguana,” which means “refreshing waters,” or “clear waters.” Initial forays into the river valley of central Texas began in the late 1600s, but were later abandoned due to the growing distrust of the local Caddoan Indians toward the Franciscan missionaries, and the murder of a leading supporter, Robert Cavelier, Sieur de La Salle. The river was christened by a Franciscan Father named Damien Massanet in June, 1691, and because it was the feast day of St. Anthony he named the site and the river for Saint Anthony of Padova. The San Antonio River valley was part of the northern periphery of Spain's colonies in the Americas.

Reoccupying the frontier in Texas began in 1716, in the San Antonio-Guadalupe rivers region because of its natural advantages such as climate and access to water. At least 30 families established the first of the towns, which was located on the San Antonio River. On May 1, 1716, Governor Alarcon designated a site on the west bank of the river for the Mission San Antonio de Valero, later called the Alamo, and a few days later chose the site for the accompanying presidio at Mission San Antonio de Bexar on San Pedro Creek. In addition to the initial settlers, a small group of Islenos—Canary Islanders who composed about 10 families out of the 400 planned—arrived after 1729.

The Spanish Crown continued to play an important role in Bexar's growth. Unsuccessful efforts to found a new settlement on the coast of Galveston Bay, and the decision to abandon surrounding missions in east Texas and move several of them to Bexar, contributed to a population boom. In 1734, the Spanish governor's residence moved to San Antonio, and in 1773 San Antonio de Bexar became the Spanish capital. By 1779, the population of San Antonio de Bexar included 80 noncommissioned officers and enlisted men, including retirees and invalids, and 191 dependents. The civilian population totaled 1,203 men, women, and children in 294 households. A third of those counted were natives of Bexar, a third were from nearby areas such as East Texas—these included various mission Indians, and the remaining third were from such far away places as Canada, Ireland, France, and of course, Spain. The population included mestizos (persons of mixed European and American Indian ancestry) and some black slaves too. The population of San Antonio supported Mexican independence in 1813, and it was significantly depopulated after the royalists purged the city of rebels.

A revolution, war, and the U.S. Civil War brought significant changes to the city. During the Texas revolution, San Antonio was the site of several battles including the most famous of the entire war, the battle of the Alamo on March 6, 1836. After the victory over Mexico, Bexar County was organized by the new republic and San Antonio became the county seat in 1837. In the aftermath of gaining independence, San Antonio was seized twice in the Mexican invasions of 1842, contributing to the declining population which by 1846 had dropped to a mere 800 residents. After it joined the Union as a slave state, the population boomed because the city became an important center for westward movement in the United States. The city had 3,488 residents in 1850, which more than doubled to 8,235 by 1860—making San Antonio the largest city in Texas.

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