The discovery of the Ob gene and its product, leptin, is a good example of the contribution made by molecular biology to the understanding of mechanisms initially hypothesized from classic physiological studies. Leptin is produced in adipose tissue and acts on the central nervous system to regulate multiple neuroendocrine secretions. In three rare cases of human morbid obesity, the discovery of mutations in the leptin and leptin receptor genes shows that leptin plays a crucial role in the control of weight and several endocrine functions (particularly reproduction). These studies also illustrate the limits of genetics in the investigation of monogenic forms of animal obesity, and the difficulties of linking molecular findings to the pathophysiology of complex diseases, such as human common obesity. Previous searches for mutations in the leptin and leptin receptor genes indicated that these are probably not major genes for common forms of human obesity. This review focuses on the recent molecular findings that have indicated a putative role for the leptin axis in human obesity.