α₂-Adrenergic receptors (α₂ARs) present in the brainstem decrease blood pressure and are targets for clinically effective antihypertensive drugs. The existence of three α₂AR subtypes, the lack of subtype-specific ligands, and the cross-reactivity of α₂AR agonists with imidazoline receptors has precluded an understanding of the role of individual α₂AR subtypes in the hypotensive response. Gene targeting was used to introduce a point mutation into the α_2aAR subtype in the mouse genome. The hypotensive response to α₂AR agonists was lost in the mutant mice, demonstrating that the α_2aAR subtype plays a principal role in this response.