It has been shown that only imidazolines and related compounds cause a fall in blood pressure when administered at the site of the hypotensive action of clonidine; no phenylethylamine compounds were capable of producing such an effect at this site. Extensive biochemical and pharmacologic studies have confirmed the involvement of imidazoline receptors in the regulation of vasomotor tone and in the mechanism of action of some centrally acting antihypertensive drugs. Imidazoline-specific binding sites (IBS) did not bind catecholamines. Functional studies using selective antagonists have confirmed that the hypotensive effects of clonidine-like drugs are mediated by imidazoline-specific receptors, whereas their sedative action clearly involves alpha2-adrenergic receptors located in the locus coeruleus. Compared with clonidine, second-generation centrally acting antihypertensive drugs such as rilmenidine have been shown to be more selective for imidazoline receptors than for alpha2-adrenergic receptors. This selectivity may explain the reduced incidence of side effects of these drugs at hypotensive doses. Very recently, new imidazoline-like compounds have been synthesized that are highly selective for both subtypes of IBS (I1 and I2). Some of these compounds lowered blood pressure when injected centrally in animals, indicating that an action on imidazoline I1 receptors alone is sufficient to lower blood pressure. With the help of such selective tools, we have also shown that imidazoline receptors and alpha2-adrenoceptors might cooperate to control vasomotor tone, and might jointly be involved in the hypotensive action of centrally acting hybrid drugs (ie, drugs that bind to both types of receptor).