Recent work in the history of science has questioned the Eurocentric nature of the field and sought to include a more global approach that would serve to displace center–periphery models in favor of approaches that take seriously local knowledge production. Historians of Iberian colonial science have taken up this approach, which involves reliance on indigenous knowledge traditions of the Americas. These traditions present a number of challenges to modern researchers, including availability and reliability of source material, issues of translation and identification, and lack of systematization. This essay explores the challenges that emerged in the author’s attempt to compile a pre-contact Nahua pharmacopeia, the reasons for these challenges, and the ways they may – or may not – be overcome.