Endothelium-derived nitric oxide is a key determinant of blood pressure homeostasis and platelet aggregation, and is synthesized by the endothelial isoform of nitric oxide synthase. In the vascular wall, endothelial nitric oxide synthase is activated by diverse cell surface receptors and by an increase in blood flow. Although initially classified as a constitutive enzyme, many substances and conditions that regulate endothelial nitric oxide synthase gene expression are now described. With the recent discovery of endothelial nitric oxide synthase being compartmentalized in signal-transducing microdomains of the plasma membrane termed caveolae, the past 2 years have mostly witnessed important advances in understanding the control of the functional expression of the enzyme.