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The Muiscas (Boyacá) and the Guane Indians (Santander) once occupied in vast numbers the regions north of what is now Bogotá. Highly developed in agriculture and mining, the Muisca traded with their neighbors and came into frequent contact with Spanish conquistadors. It was their stories of gold and emeralds that helped fuel the myth of El Dorado. The conquistadors' search for the famed city also sparked settlements and the Spanish founded several cities, including Tunja in 1539.

Several generations later, Colombian nationalists first stood up to Spanish rule in Socorro (Santander), stoking the flames of independence for other towns and regions. It was also in here that Simón Bolívar and his upstart army took on Spanish infantry, winning decisive battles at Pantano de Vargas and Puente de Boyacá. Colombia's first constitution was soon after drawn up in Villa del Rosario (Norte de Santander), between the Venezuelan border and Cúcuta.