Though indigenous communities have undergone rapid economic integration in the last few decades as a result of neoliberal reforms and increased migration, these communities experience a complex epidemiological profile that includes fetal and childhood undernutrition and adult obesity and diabetes. We argue here that the interaction of these burdens and the social conditions that have dismantled local food systems and propelled out-migration best explain the growing rate of diabetes in this region. We contrast this syndemic approach with the Thrifty Genotype Hypothesis, which attributes the high rate of diabetes among Native American populations to presumed genetic predisposition, triggered by lifestyle changes. We find the Thrifty Phenotype Hypothesis useful for explaining links between fetal and postnatal nutrition interruptions and chronic diseases in later life in certain populations and that a syndemics framework is useful for modeling the complex social causes of this pattern. While the syndemics model has largely been used to understand infectious diseases and addiction, social scientists have yet to use the framework to investigate the complex interactions between chronic malnutrition, metabolic syndrome, and political economy in rural Oaxacan communities. The most effective efforts to reduce diabetes will be those that address the social determinants of diabetes in this and other similar populations, rather than programs that address individual behaviors and lifestyle.