Some areas of the mammalian CNS, such as the retina, contain not one but two fast inhibitory neurotransmitter systems whose actions are mediated by GABA and glycine. Each inhibitory receptor system is encoded by a separate gene family and has a unique set of agonists and antagonists. Therefore, in rat retinal ganglion cells we were surprised to find that a single agent, extracellular glutathione, was capable of modulating currents activated by either GABAA or glycine receptor stimulation. Both oxidized and reduced glutathione influence inhibitory neurotransmission in a manner similar to that of the sulfhydryl redox agents dithiothreitol (DTT) and 5,5′-dithio-bis-(2-nitrobenzoic acid) (DTNB). Remarkably, the actions of glutathione are diametrically opposed on the GABAA and glycine systems. In whole-cell recordings of single retinal ganglion cells with patch pipettes, reduced glutathione enhances GABA-evoked currents but decreases glycine-evoked currents. These findings suggest that endogenous redox agents, such as glutathione, may constitute a novel modulatory system for the differential regulation of inhibitory neurotransmission in the mammalian retina.