The Indian, Hispanic and Anglo cultures that are largely responsible for Santa Fe's uniqueness haven't always existed as harmoniously as they do today. In 1610 the Spanish established Santa Fe as the capital of Nuevo Mexico and began the process of converting the area's Pueblo Indians to Catholicism. The governor of the colony, Pedro de Peralta, built the Palace of the Governors to house newcomers, mostly Franciscan friars and military personnel. From there, settlers fanned out, farming and erecting churches by using the labour of subjugated Indians.

Indian religious ceremonies were prohibited and the missionaries dealt severely with resistors. Indian leaders were flogged, enslaved or hanged and revolts were common. The San Juan leader, Popé, organised widespread resistance from a hide-out in the Taos Pueblo. In August 1680, Indians began killing Spanish priests and settlers and burning churches. Terrified settlers took refuge inside the palace and were eventually driven 482km (300mi) away to what is now Juárez, Mexico. The Indians took over Santa Fe, holding on until 1692 when Spanish troops led by Diego de Vargas recaptured the city. Traditional Indian practices were tolerated and the region flowered in relative peace throughout the 18th century.

Spain granted independence to Mexico in 1821. Led by the entrepreneurial trapper and trader William Becknell, American merchants and settlers started arriving in wagonloads. In 1846, the USA declared war on Mexico and, after the Treaty of Guadalupe Hidalgo was signed in 1848, Texas, New Mexico, Arizona and California became property of the US. Settlers from the east flocked to New Mexico, especially after it was declared a US territory in 1851, and again when the railroad arrived in 1879.