The majority of pharmacological agents are designed to accomplish a specific effect based on the established mechanisms of a disease. However, there are a few examples in which investigation of a pharmacological action has led to a previously unknown mechanism, i. e. the drug effect was observed initially before its mechanism became known. For example, the opiates had been in use for their analgesic effect for centuries before the question of endogenous substances that might explain the presence of opiate binding sites in the central nervous system (CNS) was raised, leading to the discovery of the opioids. A somewhat analogous development has occurred in another investigative arena, the observation that the administration of the benzodiazepine antagonist, flumazenil, has reversed the encephalopathy of hepatic failure. This has refocused research to discover whether one or more endogenous substances that bind to the benzodiazepine receptor in the CNS are responsible for the inhibition of CNS function of advanced liver failure. The investigative impetus was initiated by observations that patients with liver failure were highly vulnerable to benzodiazepines; therapeutic dosages precipitated coma or near-coma, and this effect was prolonged. The question was raised whether any given patient presenting with a coma-like state associated with advanced liver dysfunction might have received a benzodiazepine in the recent past, under circumstances overlooked or not recorded, that might be a contributing factor to the patient's condition. This led to testing the effects of the antagonist, with transitory success in arousing patients or improving their level of stupor. Further inquiry revealed that this improvement in mental function occurred in the absence of prior exposure to benzodiazepines. There followed a search for endogenous substances capable of binding to the benzodiazepine receptor, with CNS inhibitory effects. These investigations have resulted in the identification of several substances that may play a role in encephalopathy and can be displaced from the CNS receptor by properly designed antagonists-an ongoing investigative effort.