Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system xc−), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Display omitted Display omitted ► Iron-dependent cell death is similar to glutamate-induced excitotoxicity ► Ferroptosis is distinct from apoptosis, necrosis, and autophagy ► Ferroptosis is triggered by inhibition of cystine uptake ► Reduced cystine uptake leads to the production of lethal lipid ROS The mechanism of drug-induced iron-dependent cell death in RAS-driven cancers relies on cystine/glutamate antiport and the accumulation of hydroxylated lipids. This type of death is similar to glutamate-induced excitotoxicity in neurons, and both types of cell death can be blocked with a specific small-molecule inhibitor called ferrostatin-1.