It is generally accepted that a drug interaction with some part of a tissue is the necessary step in producing a biological response. This component of the cell has been referred to as a receptor. More than a century ago, the study of the interaction between atropine and pilocarpine on salivary flow in cats led Langley (1) to suggest that “… There is some substance or substances in the nerve endings or gland cells, with which both atropine and pilocarpine are capable of forming compounds … according to some law of which their relative mass and chemical affinity for the substance are factors”. This was probably the first expression of the “receptor concept”. Later Langley (2) concluded that “… There is evidence that the majority of substances which are ordinarily supposed to act upon nerve endings (such as nicotine, curari, atropine, pilocarpine, strychnine) act upon the receptive substances of the cells,“ i.e., upon the receptors. Ehrlich (3) might not have been aware, but he suggested that there is some substance or substances, named receptors, that are located on the surface of the nerve endings and gland. Nowadays we would name these “substances” pre- and postsynaptic receptors. The impact of the receptor theory of Langley and Ehrlich on pharmacology and drug research was very limited in their lifetimes. After 1960, receptor theory became a major area of research interest in pharmacology. The search for receptors and organ selective drugs which either mimic the action of endogenous modulators/transmitters or prevent their effect is very promising, and this field of research has made great advances in the last few years. Since Ahlquist's (4) discovery that receptors sensitive to noradrenaline (NA) can be classified as α- and β-adrenoceptors, there has been a significant progress in the pharmacology of these receptors, receptors considered to be localized on the effector cells, i.e. postsynaptically. As far as the presynaptic receptors are concerned, it has been shown by Paton and Vizi (5), that α-adrenoceptors can be localized on the axon terminals of cholinergic neurons, i.e. presynaptically. In their experiments, whereas adrenaline and NA exerted an inhibitory effect on axonal stimulation-evoked release of acetylcholine, phenylephrine had no effect. That time these compounds (adrenaline, NA, and phenylephrine) were considered as α-adrenoceptor agonists. Therefore, our finding was an early indication that the pharmacology of the pre- and postsynaptic α-adrenoceptors is different. In addition, Starke (6) provided evidence that NA sensitive receptors influencing the release of NA are not identical with the myocardial phenylephrine receptors. He stated: “The receptors influencing the secretion of norepinephrine are not identical with the myocardial phenylephrine receptors”. In 1974 Langer (7) suggested, that the pre- and postsynaptic receptors sensitive to NA are pharmacologically different. He designated them α1- and α2-adrenoceptors. Recent evidence indicates, however, that both α1- and α2-adrenoceptors can be localized on both sides, i.e. there are α1- and α2-adrenoceptors both pre- and postsynaptically. This led Berthelsen and Pettinger (8) to propose that classification of α-adrenoceptors be based on relative potencies of selective α-agonist and antagonists and not on anatomical localization. Since then drugs have been developed with selective agonist and antagonist effect on these receptors. At α1-adrenoceptors, prazosin is the most selective, whereas, at the α2-adrenoceptors, CH-38083 (7,8-(methylenedioxy)-14-α-hydroxyalloberbane) is the most selective antagonist (9–12). Currently, the issue is not whether there are two α-adrenergic receptors, but how many different subclasses there are in pre- and postsynaptic sites of α1- and α2-adrenoceptors. The possibility that differences may exist between the prejunctional effect of clonidine and noradrenaline on α2-adrenoceptors, was suggested (13–15). Ligand binding studies also suggested heterogeneity of α2-adrenoceptors (cf. 16–18). Low and high affinity [3H]clonidine binding sites could be discriminated in both saturation and kinetic experiments (cf. 19). In addition, Mottram (20) reported that yohimbine had a differential antagonistic activity against clonidine- and α-methyl-noradrenaline-induced inhibition of the contractions of the rat vas deferens elicited by field stimulation. Evidence has been obtained (21) that there are two distinct α2-adrenoceptors mechanisms involved in the prejunctional control of chemical neurotransmission. In the presence of prazosin there is an apparent dissociation of presynaptic α2-adrenoceptors: those sensitive to NA became yohimbine resistant while those sensitive to xylazine were not changed.