Over the past two decades, research has identified extrasynaptic GABA_A receptor populations that enable neurons to sense the low ambient GABA concentrations present in the extracellular space in order to generate a form of tonic inhibition not previously considered in studies of neuronal excitability. The importance of this tonic inhibition in regulating states of consciousness is highlighted by the fact that extrasynaptic GABA_A receptors (GABA_ARs) are believed to be key targets for anesthetics, sleep-promoting drugs, neurosteroids, and alcohol. The neurosteroid sensitivity of these extrasynaptic GABA_ARs may explain their importance in stress-, ovarian cycle-, and pregnancy-related mood disorders. Moreover, disruptions in network dynamics associated with schizophrenia, epilepsy, and Parkinson's disease may well involve alterations in the tonic GABA_AR-mediated conductance. Extrasynaptic GABA_ARs may therefore present a therapeutic target for treatment of these diseases, with the potential to enhance cognition and aid poststroke functional recovery.