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As large numbers of Europeans arrived in the Americas in the early 16th century, they sought to fit the unfamiliar plants, animals, and cultural practices they encountered into familiar intellectual categories. Of central importance was the category ‘natural’, key to the development of natural philosophy and a significant lens through which European thinkers would encounter and judge indigenous American knowledge over the first century of colonization. This presentation will use a selection of cases to assess how the lens of the natural (understood in opposition to the supernatural) was used to restructure areas of knowledge in which European and indigenous American beliefs met, mixed, and sometimes clashed in early modern New Spain. Indigenous Nahua systems for understanding the properties of medicinal plants, for example, did not map cleanly on to European conceptions of the natural or the supernatural. Attempts by Spanish physicians and friars to categorize them as such carried practical weight, as a supernatural categorization could incur problems with the new religious authorities. At the same time, the introduction of these categories - along with novel Eurasian plants - into existing Nahua medical and ritual systems would have consequences for their continued development through the colonial period.