The induction of caspase-independent cell death by killer lymphocytes involves the serine protease granzyme A (GzmA). In this issue, Martinvalet et al. (2008) show that GzmA penetrates the mitochondrial matrix without perturbing normal mitochondrial functions. In the mitochondrial matrix, GzmA cleaves NDUFS3 (a component of the electron transport chain) leading to production of reactive oxygen species and ultimately to cell death.