The incidence of obesity has increased sharply in recent years, making it one of the most urgent public health concerns worldwide. The hormone leptin is the central mediator in a negative feedback loop regulating energy homeostasis. Leptin administration leads to reduced food intake, increased energy expenditure, and weight loss. Leptin also mediates unique metabolic effects, specifically depleting lipid from liver and other peripheral tissues. While elucidation of leptin's role has permitted a more detailed view of the biology underlying energy homeostasis, most obese individuals are leptin resistant. A more complete understanding of the molecular components of the leptin pathway is necessary to develop effective treatment for obesity and the Metabolic Syndrome. We review here studies on the identification of one such component, stearoyl-CoA desaturase-1 (SCD-1), as a gene specifically repressed by leptin and discuss the role of this process in mediating the metabolic effects of leptin. Data indicate that pharmacologic manipulation of SCD-1 may be of benefit in the treatment of obesity, diabetes, hepatic steatosis, and other components of the Metabolic Syndrome.