Type 2 diabetes refers to a group of disparate metabolic diseases, which are typically characterized by insulin resistance in peripheral tissues, together with impaired insulin secretion from pancreatic beta-cells. The complexity of type 2 diabetes is related to factors such as genetic heterogeneity, interactions between genes, and the modulating role played by the environment. Recent progress has included defining the molecular basis of monogenic forms of type 2 diabetes, such as familial partial lipodystrophy and the subtypes of maturity-onset diabetes of the young (MODY), and also the identification of chromosomal regions that may harbor type 2 diabetes susceptibility genes. Many common variants in functional and positional candidate genes, including ADRB3, PPARG, ENPP1, and CAPN10, have also been studied for their possible role as determinants of type 2 diabetes, with varying levels of agreement between studies. The availability of a relatively complete sequence of the human genome will increase the amount of genetic information that can be used to evaluate hypotheses for the genetic basis of type 2 diabetes. To make sense of human type 2 diabetes in the post-genomic era, it is essential to have well-defined phenotypes in addition to sufficient numbers of individuals with the appropriate pedigree structure from families and/or communities.