Obesity is a significant health problem due to its serious medical complications that include hypertension, insulin resistance, diabetes, coronary artery disease, and heart failure. This review addresses the hypothesis that stearoyl-CoA desaturase (SCD) is an important metabolic control point in body weight regulation. SCD is the rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids. These products are the most abundant fatty acids found in triglycerides, cholesterol esters, wax esters, and phospholipids. Mice with a disruption in the scd1 gene (scd1(-/-)) have increased energy expenditure, reduced body adiposity, and increased insulin sensitivity, and are resistant to diet-induced obesity. The expression of several genes encoding enzymes of lipid oxidation is upregulated, whereas genes encoding enzymes of lipid synthesis are down regulated in the scd1-deficient mice. scd1 is also a component of the novel metabolic response to the hormone leptin. SCD therefore appears to be an important metabolic control point, and inhibition of its expression could be of benefit in the treatment of obesity, diabetes, cardiovascular disease, and other metabolic diseases.