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Founded in 1551 by Pedro de Valdivia, menaced constantly by Mapuches, and devastated by earthquakes in 1730 and 1751, Concepción moved several times before settling at its present site in 1764. After a major Mapuche uprising in 1598, Spain never again seriously contested Mapuche control of the area south of the Río Biobío, and Concepción remained one of the empire's southernmost fortified outposts.

After independence, Concepción's isolation from Santiago, coupled with the presence of lignite (brown coal) near Lota, a coastal town south of Concepción, fomented an autonomous industrial tradition. The export of wheat for the California gold-rush market further spurred the area's economic growth. The railway reached Concepción in 1872 and, after the Mapuche threat receded, the government bridged the Biobío to improve access to the mines and give the city a strategic role in the colonization of La Frontera, the present-day lakes region.

Traditionally left wing, particularly at the Universidad de Concepción, the city was a bulwark of support for Marxist President Salvador Allende and his Unidad Popular party. This also meant it suffered more than other regions under the military dictatorship of 1973 to 1990.