The most usual hypothesis to explain the central hypotensive effect of clonidine-like substances was to admit that these drugs stimulated alpha 2-adrenoceptors within the brainstem. Now it has been demonstrated that neither the endogenous ligand to the alpha-adrenoceptors, noradrenaline, nor any other catecholamine or phenylethylamine was hypotensive in the medullary nucleus reticularis lateralis, where all imidazolines proved to be such. Recently, a membrane receptor population sensitive to clonidine and insensitive to catecholamines was described within the nucleus reticularis lateralis; this subgroup of receptors represented 20 to 30 percent of the [ 3H]clonidine binding sites in the bovine nucleus reticularis lateralis and 100 percent within the human nucleus reticularis lateralis region. Thus, the existence of such imidazoline specific receptors was clearly established and the endogenous ligand for those receptors, which is neither a catecholamine nor likely a peptide, is under processing for purification. Therefore, it appeared that the hypotensive effect of substances with an imidazoline or imidazoline-like structure might be due to their action within medullary receptors specific for this endogenous ligand temporarily named “clonidine displacing substance.” Rilmenidine, structurally close to imidazolines, also interfered with these receptors. The central component of its hypotensive effect was recently confirmed in rabbits, where its central cardiovascular effects were antagonized by “the clonidine displacing substance.” Although exhibiting a lower affinity than the reference substance for these receptors, rilmenidine might have a higher selectivity, thus explaining its restricted side effects. A structure-activity study with this molecule would bring a confirmation to these first observations.