Hyperglycemia of type 2 diabetes mellitus (T2DM) results from a complex interplay of genetic and environmental factors that influence a number of intermediate traits (e.g., beta-cell mass, insulin secretion, insulin action, fat distribution, obesity). The primary biochemical events leading to diabetes are still unknown in most cases. Although several monogenic forms of diabetes have been identified, T2DM seems to be a polygenic disorder in the majority of cases. T2DM is probably also multigenic, meaning that many different combinations of gene defects may exist among diabetic patients. Significant results were obtained in the identification of the genetic determinants of monogenic forms of diabetes with young age of onset. However, despite the evidence for a strong genetic background, little of the genetic risk factors for the more-common forms of polygenic T2DM are known to date. The goal of this chapter is to summarize and discuss the significant results of recent literature on the genetics of both the monogenic and polygenic forms of T2DM.