A key and highly regulated enzyme that is required for the biosynthesis of monounsaturated fatty acids is stearoyl-CoA desaturase (SCD) that catalyzes the D⁹-cis desaturation of a range of fatty acyl-CoA substrates. The preferred substrates are palmitoyl- and stearoyl-CoA, which are converted into palmitoleoyl- and oleoyl-CoA respectively. Oleate is the most abundant monounsaturated fatty acid in dietary fat and is therefore readily available. Studies of mice that have a naturally-occurring mutation in the SCD-1 gene isoform as well as a mouse model with a targeted disruption of the SCD gene (SCD-1^-/-) have revealed the role of de novo synthesized oleate and thus the physiological importance of SCD-1 expression. SCD-1 deficiency results in reduced body adiposity, increased insulin sensitivity, and resistance to diet-induced obesity. The expression of several genes of lipid oxidation are upregulated, whereas lipid synthesis genes are downregulated. SCD-1 was also found to be a component of the novel metabolic response to the hormone leptin. SCD-1 therefore appears to be an important metabolic control point and inhibition of its expression could be of benefit for the treatment of obesity, diabetes and other metabolic diseases. In this chapter we summarize the recent and timely advances concerning the important role of SCD in the biochemistry and physiology of lipid metabolism.