Cycads (Cycadales) are a prehistoric order of gymnosperms with origins in the early Permian period some 300 Mya, four genera of which are endemic to the Americas, with three represented in Mexico. Although never domesticated, archaeological, historical, and ethnographic data suggest that in ancient Mesoamerica and modern Mexico these plants have played, and continue to play, significant though undervalued roles in regional cultures. The lack of scholarly attention to cycads in these contexts appears to stem from their rapidly decreasing populations and toxicity, which has seemingly diverted attention away from cycads, despite considerable evidence indicating their utilitarian and symbolic use from the Pleistocene–Holocene transition to the present. As a botanical resource that thrives in diverse ecosystems, cycads in Mexico are used in a variety of ways and figure prominently in indigenous horticulture, foodways, and cultural practices, in which they are often conceptually associated with maize. This contribution speaks to this underappreciated and now often critically endangered plant. Drawing on a range of data and disciplinary perspectives—from genomics to archaeology to contemporary ethnography—it explores the place of cycads in ancient and modern Mexican cultural landscapes and agroecological systems, particularly their enduring relationship to maize and the maize preparation complex. Thus, the paper unpacks associations between cycads and multiple ecological and cultural components to illustrate both the environmental and social roles of cycads, as well as the shifting indigenous epistemologies and ethnoecologies in which these plants were, and remain, imbricated. It concludes by highlighting similarities between cycad-human relationships in Mexico and those in other world regions, including Japan. In doing so, it illuminates a unique and endangered form of biocultural heritage to enhance our understanding of the significance of the ancient and modern practices that incorporated this natural-cultural hybrid and the larger cultural systems in which cycads formed a critical component, and to incentivize the study and conservation of cycad cultures in Mexico and beyond.