There is no doubt that the sympathetic nervous system (SNS) plays an important role in the pathogenesis and maintenance of hypertensive disease, although many details concerning this association remain to be clarified. Over the years, several types of antihypertensive drugs have been developed that can impair SNS activity at virtually all levels of the system, α- and β-adrenoceptor antagonists, postganglionic sympathetic neuron blockers and ganglioplegic agents are well-known examples of drugs with a predominantly peripheral activity. The CNS regulation of peripheral sympathetic activity offers a further possibility to counteract the influence of SNS activity. In particular, central catecholaminergic neurons and α2-adrenoceptors have been analyzed in detail and are recognized as important targets for the classic centrally acting antihypertensives clonidine, guanfacine, and α-methyldopa. Initially, these drugs were assumed to reduce elevated blood pressure via the stimulation of central α2-adrenoceptors in the brainstem, thus leading to peripheral sympathoinhibition and a reduction of elevated blood pressure, heart rate, and plasma catecholamines. In a later stage it has been recognized that central imidazoline (I1) receptors may also be involved in the central regulation of peripheral sympathetic activity and that they act as a target for centrally acting antihypertensives. Moxonidine and rilmenidine are the prototypes of such agents. Accordingly, the receptor profile of the various types of centrally acting antihypertensives can be characterized as follows: α-methyl-DOPA (through α-methylnorepinephrine) α2; clonidine (mixed agonist), α2 + I1; moxonidine, rilmenidine, I1 > α2. The various compounds mentioned will thus cause peripheral sympathoinhibition, initiated by different receptor targets in the CNS. Because most of the adverse reactions to clonidine and related drugs are mediated by central α2-adrenoceptors, it is hoped that the imidazoline receptor agonists (moxonidine, rilmenidine) will show a more favorable pattern of side effects.