Apoptosis is a type of cell death whose morphological appearance relies on the activation of caspase-family cysteine proteases. Recently, it has become clear that inhibition of caspases does not always prevent irreversible loss of cellular function, although it does prevent the acquisition of apoptotic morphology. Alterations in mitochondrial membrane structure and function can occur in a caspase-independent fashion and have a higher predictive value for cell death than caspase activation. Here, Douglas Green and Guido Kroemer argue that caspases might have a dual function in the apoptotic process: first, as signal-transduction molecules that act as facultative inducers of mitochondrial membrane changes, and, second, as processing enzymes that orchestrate the apoptotic phenotype. They propose a model for initiation of apoptosis in which mitochondria and caspases engage in a self-amplifying pathway of mutual activation.