When injected into the medullary site of the hypotensive action of clonidine, imidazolines and related compounds decrease blood pressure (BP), whereas no phenylethylamine compounds were capable of producing such an effect at the same site. There is much biochemical and pharmacologic evidence to support the involvement of imidazoline receptors in the regulation of vasomotor tone as well as in the mechanism of action of some centrally acting antihypertensive drugs. Imidazoline-specific binding sites, which do not recognize catecholamines, have been described in various tissues. Functional studies using selective antagonists have confirmed that the hypotensive effects of clonidine-like drugs are mediated, at least in part, by nonadrenergic imidazoline-specific receptors, whereas their sedative action clearly involves alpha2-adrenergic receptors located in the locus coeruleus. Compared with clonidine, newer centrally acting antihypertensive drugs such as rilmenidine are more selective for imidazoline receptors than for alpha2-adrenergic receptors. This selectivity may explain the reduced incidence of side effects of these drugs at therapeutic doses. Very recently, imidazoline-like compounds with no affinity and no activity at alpha2-adrenergic receptors have become available. Some of these compounds lowered the BP when injected centrally, indicating that an action on imidazoline I1 receptors alone is sufficient to cause hypotension. Nevertheless, imidazoline receptors and alpha2-adrenoceptors cooperate in the control of the vasomotor tone and in the hypotensive action of centrally acting hybrid drugs (ie, drugs that bind to both types of receptor). Additional noncardiovascular effects of imidazoline-like drugs have also been described, such as insulin secretion stimulation and renal sodium reabsorption inhibition. These effects may account for the long-term benefits of imidazoline selective drugs, such as rilmenidine.