alpha(2)-Adrenergic receptors (alpha(2)ARs) are essential components of the neural circuitry regulating cardiovascular function. The role of specific alpha(2)AR subtypes alpha(2a), alpha(2b), and alpha(2c) was characterized with hemodynamic measurements obtained from strains of genetically engineered mice deficient in either alpha(2b) or alpha(2c) receptors. Stimulation of alpha(2b) receptors in vascular smooth muscle produced hypertension and counteracted the clinically beneficial hypotensive effect of stimulating alpha(2a) receptors in the central nervous system. There were no hemodynamic effects produced by disruption of the alpha(2c) subtype. These results provide evidence for the clinical efficacy of more subtype-selective alpha(2)AR drugs.