Fajardo was the son of a Spanish lieutenant of the same name and an indigenous Indian woman, Isabel of the Guaiquerí. In 1555 to 1557 he made several expeditions from Margarita to conquer the Caracas tribe (near present-day Caracas). As a mestizo (person of mixed race) he was able to blend in with the indigenous tribes of the coast physically and culturally. After murdering a local cacique he had to flee back to Margarita in 1558.
He returned to the mainland in 1560, becoming lieutenant-general of Valencia, Venezuela, before going back to Margarita to defend it against Lope de Aguirre. On a new expedition to the mainland he discovered a gold mine in the territory of the Teques, in the Caracas region near present-day Los Teques. Early attempts at settlement had to be abandoned in 1562 when an uprising led by Guaicaipuro forced Fajardo to retreat again to Margarita, an expedition by Luis de Narváez to reinforce Fajardo having been destroyed.
After setting out on a new expedition from Margarita in 1564, he was arrested and executed in Cumaná by Alonso Cobos after a sham trial. Cobos was arrested in Cumana by outraged residents of Margarita, and after a trial in Margarita was executed for the murder of Fajardo.
- Juan Ernesto Montenegro (1974), Francisco Fajardo: origen y perfil del primer fundador de Caracas, Caracas: Concejo Municipal del Distrito Federal
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