Globally, the increase in Type 2 Diabetes (T2D) prevalence represents a complex public health problem, particularly in developing countries, including Mexico. Type 2 diabetes results from an interaction between genetic predisposition and drastic changes in lifestyle. The aim of this review is to explore these interactions on T2D development, using the Mexican and US Pima Indians comparative study as a model; two genetic related groups, living in different environments, and Mexican Pimas and non-Pimas (Blancos) sharing a similar environment, but not the genetics. Study results showed a lower T2D and obesity prevalence in Mexican Pimas when compared with US Pimas. Likewise, Mexican Pimas had lower fat consumption, higher dietary fiber and higher physical activity than their counterparts in the US. The Pima Indians study showed that even in genetically predisposed populations, T2D development could be mainly determined by lifestyle related factors.