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Before Spanish arrival, the Guane people inhabited the highland valleys of what's now Santander, developing agriculture, weaving, and pottery traditions distinct from other Indigenous groups in the wider region. Spanish colonization from the mid-16th century established towns throughout the department, with tobacco quickly becoming the region's dominant colonial-era export crop.
Santander holds a specific place in Colombian political history: the Revolt of the Comuneros in 1781, a tax-protest uprising centered in the town of El Socorro, is remembered as an important precursor to Colombian independence from Spain, decades before independence was actually achieved in the 1810s-1820s. The revolt was ultimately suppressed, but its memory became part of the department's own identity as historically independent-minded.
Through the 19th and much of the 20th century, Santander's economy remained centered on tobacco and small-scale agriculture, with towns like Barichara seeing relatively little new construction or population growth -- a economic stagnation that, decades later, became a preservation advantage once Colombia's tourism industry rediscovered these towns' intact colonial architecture.