Type 2 diabetes (T2DM) comprises a group of entities with different genetic causes. In most patients, T2DM results from alterations of various genes, each having a partial and additive effect. The inheritance pattern is thus complex, and environmental factors play an important role in favoring or delaying the expression of the disease. The identification of susceptibility genes and genetic variants requires different methodological approaches. Here we address some of the most important strategies and findings on the genomic basis of T2DM, as well as evidence of genetic heterogeneity among populations. The identification of the underlying genetic causes of T2DM and other related traits such as obesity and hypertension will lead to the development of new therapeutic targets likely to impact the way we treat these diseases. Survival and quality of life for T2DM patients is expected to eventually increase, significantly lessening the socioeconomic burden of the disease.