According to most accounts, the Spanish conquest decimated and nearly obliterated the region’s Indigenous populations. Genetic evidence from the isthmus, nevertheless, has pointed to an 80% indigenous maternal legacy in Panama’s present-day population. While common in Central and South America, sex-biased admixture led to the legal exportation of enslaved indigenous males but not females from the isthmus, reflecting and reinforcing the invaders’ dependency on local women’s labor and knowledge. Further evidence that the indigenous or Cueva population did not simply disappear comes from historical records of indigenous women’s unions with Spanish and African men. When consensual, such alliances provided newcomers pursuing “the secrets of the land” commercial and military aid. While relying upon such support, Spanish rarely recorded the importance of marriage, warfare, and trade for affirming legitimacy in the region, and even more rarely acknowledged the value of polygamy, polyandry, and matrilineal inheritance in the societies they encountered.