The rapid increase of diabetes prevalence in the US population and across all westernized world has been associated with environmental changes that promote obesity. However, studies conducted in various ethnic groups within the US population have pointed out differences in susceptibility to diabetes within the same environmental pressure. Of particular interest is the growing evidence that Asian Indians, i.e., persons originating from the Indian Subcontinent, are at uniquely heightened risk for type 2 diabetes when compared to other populations. The elucidation of the mechanisms responsible for the heterogeneous relationship between obesity and type 2 diabetes in various ethnic groups, and particularly in Asian Indians, may give important contributions to better understand the complex mechanisms involved in the development of type 2 diabetes. This review examines epidemiological and pathophysiological aspects of the interaction between environment and ethnic predisposition to type 2 diabetes in Asian Indians migrated to the US.