The prevalence of type 2 diabetes in Canadian Oji-Cree is among the highest in the world. Our research has uncovered genetic determinants of Oji-Cree type 2 diabetes and related metabolic traits. The most important genetic discovery by far was the private G319S mutation in transcription factor HNF-1alpha, encoded by the HNF1A gene. HNF1A G319S was discovered by candidate gene sequencing and would have been missed using the currently favored strategy of genome-wide scanning. G319S was associated with increased odds of having type 2 diabetes across the whole study sample and in all subgroups, including adolescent Oji-Cree. Furthermore, G319S had specificity and positive predictive value of 97% and 95%, respectively, for developing type 2 diabetes by age 50. The protein bearing the G319S mutation had impaired function in vitro. Sigmoidal modeling showed that each dose of the G319S allele accelerated the median age of diabetes onset by about 7 yr. This approach also showed that environment more strongly accelerated the median age-of-onset of Oji-Cree diabetes onset than did G319S, which could have implications for intervention strategies to reduce the burden of this epidemic. There is also evidence for genetic determination of related metabolic traits in the Oji-Cree.