ABSTRACT: There has been a continuing and yet unresolved debate concerning the existence and contribution of imidazoline receptors to the antihypertensive actions of clonidine-like agents. Studies from our laboratory have examined the importance of imidazoline receptors and α2-adrenoceptors in the mechanism of action of centrally acting antihypertensive drugs. We used conscious rabbits and imidazoline and specific α2-adrenoceptor antagonists to show that second-generation agents rilmenidine and moxonidine act preferentially through imidazoline receptors but that α2-adrenoceptors are important for the hypotension produced by clonidine and α-methyldopa. Using microinjections of the imidazoline antagonists into the rostral ventrolateral medulla (RVLM) of anesthetized rabbits we confirmed the generally held view that this is the major site of sympathoinhibitory actions of centrally acting antihypertensive agents. However, we also found that α2-adrenoceptors are present in this nucleus and appear to be activated as a consequence of imidazoline receptor activation. In recent studies using a noradrenergic neurotoxin microinjected into the RVLM we found that this treatment selectively blocked the actions of moxonidine but did not affect the level of imidazole proteins, suggesting that I1-imidazoline receptors may be located presynaptic to the noradrenergic terminal. By contrast, clonidine acts directly on the α2-adrenoceptors perhaps located on cell bodies in the nucleus. In conclusion, our studies suggest that imidazoline receptors and α2-adrenoceptors within the RVLM are important for the antihypertensive actions of clonidine-like drugs.