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Objective: Analyze the emergence of diabetes mellitus (DM) in isolated Amerindian communities in Oaxaca, southern Mexico.Background: DM is increasing in prevalence worldwide, and Amerindian populations are particularly susceptible.Methods: Surveillance data of DM in Oaxaca were collected from 1950 to 2010.Data for adult overweight (OW) and obesity (OB) were collected from 1960s to 2002.The analytical framework is partitioning phenotypic variance into genetic, environmental, and gene-environment interaction.Results: Prevalence of DM has increased from <1% (1950) to >16% in Oaxaca (2010).Three major risk factors for DM emerge: family history (four-fold increased risk), OW/OB (four-fold increased risk), and stage of the community in the epidemiologic transition (two-fold increased risk).Conclusion: These results are consistent with DM being the result of environmental trigger(s) activating a genetic susceptibility through gene-environment interaction.