Type 2 diabetes has become a leading health problem throughout the world. The escalating epidemic of type 2 diabetes is believed to result from a collision between inherent biological susceptibilities (genotypes) and a shift toward dietary habits and lifestyle that promote obesity over the past several decades; the transition from "traditional" to modern "obesogenic" lifestyles is characterized by widespread access to highly palatable, nutrient-deficient, and calorie-dense foods and beverages, as well as circumstances that promote sedentary behaviors and inhibit physical activity. In the past decades, a large body of epidemiological studies has associated various dietary factors with type 2 diabetes risk. In the meantime, genetic studies have made great strides in unraveling the genetic basis of type 2 diabetes by identifying more about 100 common genetic loci related to the disease. Nutrigenetics, a relatively new branch of nutrition science, focuses on determining the interplay between dietary exposures and genetic factors in the etiology of many diseases including type 2 diabetes. Even with many hundreds of gene-diet/lifestyle interaction studies on diabetes-related traits published over the past two decades, few examples have been adequately replicated or validated. By contrast, a number of replicated examples of interactions between lifestyle factors (e.g., consumption of sugar sweetened beverages and fried foods and low physical activity and sedentary lifestyles) and genetic factors in obesity (a major risk factor for diabetes) have recently emerged. Further advances are likely to come from the optimization of methods and study designs for nutrigenetic analyses. The development of methods to integrate genetic, transcriptomic, epigenomic, proteomic, and metabolomic data to help define the functional mechanisms that might underlie observations of gene-lifestyle interactions is an especially exciting, yet challenging, area. Nutrigenetic studies hold great promise to inform personalized diet and lifestyle interventions to reduce type 2 diabetes risk and improve human health; however, deriving replicated examples of such interactions and determining how best to translate these findings into public health practice and medical intervention remain major challenges.