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Traditionally known as Santa Cruz de Mompox, the town was founded in 1537 on the eastern branch of the Río Magdalena, which in this part has two arms, Brazo Mompós and Brazo de Loba. The town's name comes from Mompoj, the name of the last cacique (tribal head) of the Kimbay Indians, who inhabited the region before the Spanish Conquest.

Mompós soon became an important trading center and active port, through which all merchandise from Cartagena passed via the Canal del Dique and the Río Magdalena to the interior of the colony. When Cartagena was attacked by pirates, Mompós served as a refuge for the families of the city's defenders.

The town flourished and several fair-sized churches and luxurious mansions were built. In 1810 Mompós proclaimed its independence from the Virreynato de la Nueva Granada; it was the first town to do so. Simón Bolívar, who stayed here for a short time during his liberation campaign, said: 'While to Caracas I owe my life, to Mompós I owe my glory.'

Towards the end of the 19th century, shipping on the Magdalena was diverted to the other branch of the river, the Brazo de Loba, bringing the town's prosperity to an end. Mompós has been left in isolation, living on memories of times gone by. Little has changed since. The town's colonial character is very much in evidence, as are the airs of a bygone era. It's fun to wander aimlessly about this tranquil town, discovering its rich architectural legacy and absorbing the old-time atmosphere.