During starvation, cells use autophagy (self-digestion) to generate nutrients essential for cell survival. However, autophagy can also promote cell death. Spencer Gibson and colleagues now reveal that the induction of this form of death in cancer cells involves the accumulation of reactive oxygen species (ROS) in mitochondria (see p. 4155). Inhibitors of the mitochondrial electron transport chain (mETC) complexes I and II [rotenone and thenoyl trifluoroacetone (TTFA), respectively] induce cell death and autophagy in U87 cells (a glioma cell line derived from astrocytes) and other transformed cells, they report, but not in primary mouse astrocytes. Rotenone and TTFA both induce ROS production and the authors show that the ROS scavenger tiron decreases the autophagy and cell death induced by these inhibitors. Knocking down the antioxidant enzyme manganese-superoxide dismutase (SOD2) by RNAi has the opposite effect. Because the autophagy-induced death only occurs in cancer cells, the authors suggest that prolonged activation of autophagy with mETC inhibitors could provide a strategy for the treatment of apoptosis-resistant cancers.