Publisher Summary The binding of a drug, such as a benzodiazepine or endogenous substance to the recognition site, is currently envisioned as initiating a series of events resulting in a pharmacologic or physiologic action. This chapter describes the recent developments on the regulation of the benzodiazepine receptor that has yielded new insights into the modes of action of agents that are structurally dissimilar to the benzodiazepines but share common therapeutic actions. One of the most important advances in probing the molecular pharmacology of the benzodiazepine receptor is the observation that a functional coupling exists between this site and a recognition site for ۄ-aminobutyric acid (GABA). Although a large body of electrophysiologic, pharmacologic, and behavioral evidence suggests that benzodiazepines facilitate the actions of the inhibitory neurotransmitter GABA, the neurochemical bases for this facilitation remain unclear. The functional association of benzodiazepine receptors with a chloride ionophore has been further strengthened by neurochemical findings from several laboratories. It has been reported that the convulsant benzodiazepine Ro-5-3663 is more potent as an inhibitor of GABA-enhanced benzodiazepine binding than in inhibiting “basal” (non GABA-stimulated) binding. Several drugs, as well as endogenous factors have now been found to possess similar characteristics. Prior to the introduction of benzodiazepines, barbiturates were widely used as anxiolytics and continue to be prescribed occasionally for this purpose. The pyrazolopyridines, demonstrated to have anxiolytic actions in experimental animals, must be given a comprehensive clinical trial to determine their efficacy as anxiolytics in man. Nonetheless, it is still premature to attempt to assign a pharmacologic action to specific changes in a benzodiazepine/GABA receptor/chloride ionophore complex.