Adrenergic receptors form the interface between the sympathetic nervous system and the cardiovascular system as well as many endocrine and parenchymal tissues. For the three alpha 2-adrenergic receptors (alpha 2A, alpha 2B, and alpha 2C), genetic mouse models have been developed that can be used to elucidate the physiologic function of each receptor subtype in vivo. Different strategies for homologous recombination in embryonic stem cells were applied to generate lines of mice with gene knockouts of the individual alpha 2-receptor subtypes (alpha 2A-KO, alpha 2B-KO, and alpha 2C-KO) or with a substitution of a mutant receptor at the wild-type locus (alpha 2-D79N). In these transgenic mice, the cardiovascular effects of alpha 2-agonists and imidazoline receptor agonists were tested. Stimulation of alpha 2B receptors in vascular smooth muscle produces hypertension and counteracts the clinically beneficial hypotensive effect of stimulating alpha 2A receptors in the central nervous system.