Although macromolecular synthesis inhibitors have been demonstrated to prevent neuronal apoptosis in a number of paradigms, their mechanisms of protection remains unclear. Recently, we found that neuronal death resulting from cystine deprivation, glutathione loss, and oxidative stress is apoptotic and is prevented by inhibitors of macromolecular synthesis. We now report that protection is associated with enhanced availability of acid-soluble cyst(e)ine and restoration of cellular glutathione levels. N-acetylcysteine, an agent that delivers exogenous cysteine intracellularly and raises glutathione, is also protective, while buthionine sulfoximine, an inhibitor of glutathione synthesis, prevents protection by inhibitors of macromolecular synthesis. These results suggest that protection provided by these agents, in this paradigm, derives from shunting of the amino acid cysteine from global protein synthesis into the formation of the antioxidant glutathione.