Although the recent pandemic of obesity is apparently driven by environmental factors, the influence of genetic factors has also increasingly been recognized. Monogenic inheritance of obesity has been documented in several human disorders and some of their etiological basis has been elucidated at the molecular level. The frequency of these monogenic diseases is generally very rare, but their elucidation gives an important insight into our understanding of the molecular basis of the more common form of human obesity. In fact, the identification of rare mutations in the genes for ligands and receptors of the leptin-melanocortin pathway established that the pathway is physiologically essential for normal homeostasis of food intake and energy expenditure.