Gamma-hydroxybutyrate (GHB) is a drug of abuse that causes euphoria, anxiolysis, and hypnosis. The recent rise in the recreational intake of GHB, as well as its association with 'drug rape', has turned the attention to GHB in acute hospital settings. Acutely admitted GHB intoxicated patients may display various levels of sedation or coma, but may also show paradoxical agitation, combativeness, or self-injurious behaviors. The symptoms can be nonspecific and the definite diagnosis therefore normally relies on the detection of GHB in blood or body fluids, which is an analysis that may not be promptly available. As a basis for understanding the clinical features of GHB intoxication and abuse, we here review the pharmacological and neurophysiological knowledge about GHB, which stems from decades of clinical and basic GHB research. In addition, we discuss the latest discoveries in the quest for distinct GHB receptors in the brain, and their possible implications for future therapies of GHB abuse.