Flumazenil is a recently discovered pharmacologic antagonist of the CNS effects of benzodiazepines. It acts by binding CNS benzodiazepine receptors and competitively blocking benzodiazepine activation of inhibitory GABAergic synapses. Animal studies and some human studies appear to demonstrate that flumazenil has weak intrinsic agonist activity; on the other hand, studies are inconclusive in demonstrating any inverse agonist effects of this agent. Evidence available suggests that flumazenil is well tolerated in human beings over a broad range of doses when given either orally or parenterally and does not produce serious adverse effects. In the setting of isolated benzodiazepine overdose, flumazenil is capable of completely reversing coma within one to two minutes, with this effect lasting between one and five hours. Repeat doses can be given safely to reverse recurrent effects of longer-acting benzodiazepines. Flumazenil is undergoing further evaluation by the Food and Drug Administration; should this drug receive approval, it is likely to be used in emergency departments as well as in a variety of other clinical settings. First, it could be used to effect rapid reversal of benzodiazepine-induced sedation that has been administered to facilitate medical, orthopedic, and surgical procedures, particularly in the event of inadvertent respiratory depression. Second, flumazenil might have a therapeutic role in the management of patients who have taken benzodiazepine overdoses. Although most of these patients can be managed successfully with supportive therapy alone, it is possible that the use of flumazenil may obviate the need for intubation and respiratory support in such patients and eliminate the possible adverse effects of even short-term endotracheal intubation. Finally, flumazenil could have both diagnostic and therapeutic value in patients with acute alterations of mental status of unknown etiology, particularly when possible drug overdose is a consideration. Because flumazenil appears to be specific in its antagonism of benzodiazepine-induced respiratory and CNS depression, it could be used empirically to confirm or exclude a role of benzodiazepines in the generation of mental status changes in the setting of overdose or coma of unknown origin. This in turn might obviate the need for further expensive (eg, computed tomography) and sometimes invasive (eg, lumbar puncture) diagnostic modalities. This might be particularly useful because there is nothing about benzodiazepine-induced coma that clearly distinguishes it from other causes of coma; thus, there are no signs or symptoms that may reasonably allow benzodiazepine overdose to be confirmed or eliminated on clinical grounds. Further studies will continue to define the ultimate use of this new agent.