Dextromethorphan is one of the most widely used non-opioid cough suppressants, representing the active ingredient in several over-the-counter antitussive formulations. It does not possess the CNS pharmacology of other opiates in humans (i.e. analgesia, respiratory depression, abuse liability or psychotomimetic properties), but since the discovery in 1981 of high affinity recognition sites in brain for dextromethorphan a unique neuropharmacological profile has emerged for this relatively innocuous drug. Anticonvulsant and neuroprotective properties have been demonstrated, and treatment with dextromethorphan has been shown to improve the cerebrovascular and functional consequences of global cerebral ischemia. Frank Tortella and colleagues review the CNS pharmacology of dextromethorphan, its possible involvement with NMDA or sigma-receptors, and the potential clinical importance of this old 'new' drug.