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A more detailed understanding of the pathogenesis of human obesity may ultimately guide treatment of affected individuals. Obesity that results from reduced melanocortins, for example, might respond well to administration of melanocortin-receptor agonists, if and when they become available in a clinical setting. Evidence for this is provided in a recent study of POMC-knockout mice, in which obesity was reversed by administration of an MC4-receptor agonist113. Analogously, administering leptin to an obese human with genetic leptin deficiency reduced weight as markedly as it does in ob/ob mice114. Obesity that is associated with leptin resistance, however, may be common and would be unlikely to respond to leptin treatment unless the resistance can be overcome. Patients with defective melanocortin-receptor function, for example, seem unlikely to respond to therapy with either leptin or melanocortin-receptor agonists. These consideration sindicate that an expanded ability to diagnose the pathophysiological basis of human obesitywillhavedirectapplicationstoitstreatment.However,amultidrug regimen that targets multiplesites within the weight-regulatory system may be necessary to achieve and sustain weight loss in many individuals. The impressive effects of AGRP on food intake in rodents62,63 indicatethatitwarrantsevaluationinthetreatmentofconditionsassociatedwith excessive weight loss, including anorexia nervosa and wasting illness associatedwith AIDS or cancer. If AGRP proves ineffective in this context, it would in dicate that the pathogenesis of such conditions involves pathways additional to, and potentially downstream of, melanocortin-receptor activation. Such an outcome might therefore direct therapeutic strategies towards activation of other candidate anabolic (or inhibition of catabolic) effect or pathways. These considerations highlight the importance of clarifying the mechanisms that controlfood intake and energy homeostasis. Such information will help us to understand the pathogenesis of disorders at both ends of the body-weight spectrum, and is a probable prerequisite for their successful treatment. The enormous cost to human health attributable to these disorders emphasizes the need for a more complete understanding of this area.