The inhibitor of apoptosis proteins (IAPs) regulate programmed cell death by inhibiting members of the caspase family of enzymes. A novel mammalian protein that binds to IAPs and neutralizes the inhibitory effect of IAPs on caspases was recently identified and designated Smac/DIABLO. Smac/DIABLO is a mitochondrial protein that is released along with cytochrome c during apoptosis and activates cytochrome c/Apaf-1/capase-9 pathway. Analysis of the structural basis of Smac/DIABLO reveals that the N-terminal amino acids are required for binding of Smac/DIABLO to IAPs and activation of caspases. Smac/DIABLO is expressed in a variety of human and mouse tissues.