In Drosophila, the genetic locus 75CI1,2 is essential for all developmental cell death. Within this region are the genes for three pro-death proteins, Grim, Reaper and HID. These proteins are transcriptionally regulated and their expression tightly associated with cell death in the developing fly embryo. When ectopically expressed in the retina, Grim, Reaper and HID cause apoptosis and eye ablation. They have a short region of similarity at their N-termini through which they can interact with inhibitor of apoptosis (IAP) proteins, and it is by antagonising IAP inhibition of caspases that Grim, Reaper and HID promote cell death. The observation that Grim, Reaper and HID can interact with mammalian IAPs and induce apoptosis in mammalian cells suggested that mammalian IAP antagonists might also exist. Diablo/Smac, identified six years after the first description of a Drosophila IAP antagonist, is the only mammalian protein identified to date that is clearly functionally related to the Drosophila proteins. Since its discovery, there have been numerous studies investigating how Diablo/Smac interacts with IAPs and promotes cell death. Here we review what is currently known about Diablo/Smac and speculate on other mammalian IAP antagonists.