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At present, the only therapeutic agent in current use that is known to exert its effects through the GABA-B receptor is baclofen, the β-chlorophenyl analog of GABA. This compound is used extensively as a centrally active muscle relaxant, but it has been shown clinically to exert additional effects, including analgesia, suppression of drug addiction, and cessation of chronic cough. Basic research indicates that there may be many other applications not only for agonists, but also antagonists at the GABA-B receptor, and this chapter seeks to examine the potential significance of these and also of allosteric modulators for the receptor, which have been recognized during the past 5 yr. GABA-B receptors have been implicated in neuronal processing in many brain regions and there is considerable evidence for their pathological involvement in various diseases of the central nervous system, such as absence epilepsy, depression, and even in the etiology of nicotine dependency in humans. Novel chemical entities will surely be the key to exploiting this receptor. At present, the only agonist (baclofen) in the clinic frequently produces unwanted side effects, and this clearly limits its usage. There are no antagonists in clinical therapy, although trials for cognition deficits are underway. Metabotropic receptors, of which the GABA-B receptor is a member, provide most of the targets for our currently used therapeutic agents; thus, there seems to be every reason to believe that the rewards for discovering clinically available GABA-B receptor ligands could be high. [ABSTRACT FROM AUTHOR]