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The prevalence of metabolic diseases in Mexicans has grown in recent decades, which increases the burden on the health system. The study of the genetics of metabolic diseases is a complex process resulting from an interaction between environmental and genetic factors. Although most genome-wide association studies for these diseases have focused on populations other than the Mexican population, genetic variants almost exclusive to populations with high Native American ancestry have been discovered, or those initially identified in different populations without Amerindian ancestry have been replicated. Therefore, the objective of this review is to present an overview of the genetics of Mexicans and their relationship with some of the most frequent metabolic diseases in this population, such as type 2 diabetes, gestational diabetes, diabetic neuropathy, obesity, and dyslipidemias.