The pharmacology of the benzodiazepine receptor is unusual in relation to other receptors in that there exist three types of ligand: agonists (e.g. diazepam), which are anxiolytic and anticonvulsant; antagonists (e.g. flumazenil), which are neutral; and inverse agonists (e.g. FG 7142), which are anxiogenic and proconvulsant. Chronic administration of agonists leads to tolerance and withdrawal, and produces a global shift in benzodiazepine receptor function with attenuation of agonist and enhancement of inverse agonist actions. These changes appear without alterations in receptor number or affinity, and may reflect a shift in efficacy, "withdrawal shift", at the receptor. Treatment with flumazenil during benzodiazepine agonist administration, or even in the period after the last dose, can prevent or reverse this efficacy shift as indicated by a lack of sensitization to inverse agonists. The clinical implications of these findings are discussed.