Obesity is associated with increased morbidity and mortality from cardiovascular disease, diabetes mellitus and certain cancers. The prevalence of obesity is increasing rapidly throughout the world and is now recognized as a major global public-health concern. Although the increased prevalence of obesity is undoubtedly driven by environmental factors, the evidence that inherited factors profoundly influence human fat mass is equally compelling. Twin and adoption studies indicate that up to 70% of the interindividual variance in fat mass is determined by genetic factors. Genetic strategies can, therefore, provide a useful tool with which to dissect the complex (and often heterogeneous) molecular and physiologic mechanisms involved in the regulation of body weight. In this Review, we have focused our attention on monogenic disorders, which primarily result in severe, early-onset obesity. The study of these genetic disorders has provided a framework for our understanding of the mechanisms involved in the regulation of body weight in humans and how these mechanisms are disrupted in obesity. The genes affected in these monogenic disorders all encode ligands and receptors of the highly conserved leptin-melanocortin pathway, which is critical for the regulation of food intake and body weight.