ABSTRACT: 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 α2-adrenergic receptors (α2A, α2B, and α2C), 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 α2-receptor subtypes (α2A-KO, α2B-KO, and α2C-KO) or with a substitution of a mutant receptor at the wild-type locus (α2-D79N). In these transgenic mice, the cardiovascular effects of α2-agonists and imidazoline;i1 receptor agonists were tested. Stimulation of α2B receptors in vascular smooth muscle produces hypertension and counteracts the clinically beneficial hypotensive effect of stimulating α2A receptors in the central nervous system.