The application of transgenic techniques to alter gene expression in vivo has provided new models to evaluate the role of specific genes in the complex pathogenesis of noninsulin-dependent diabetes mellitus (NIDDM). In this review, we summarize methods used to create transgenic animals and highlight results from those models which have contributed to our understanding of the overall pathophysiology of NIDDM. Transgenic animal models have clearly demonstrated the requirement for normal insulin action in skeletal muscle, adipose tissue, and liver, as well as normal insulin secretion by the pancreatic β-cell, in the maintenance of glucose homeostasis. In addition, these data confirm that isolated defects in single critical genes, including the insulin receptor, IRS-1, and glucokinase, may play a role in the development of some types of insulin resistance and NIDDM. However, it is likely that multiple additive defects, both genetic and acquired, are required to produce the full clinical syndrome typical of more common forms of NIDDM.