Eukaryotic cells use complex networks of signal transduction proteins to make decisions about whether to differentiate, grow or die. In the case of apoptosis, which is responsible for the programmed death of unwanted or damaged cells in multicellular organisms, recent structural, biochemical and cell-based assays have enhanced our understanding of the mechanisms by which some of the key proteins regulate this process. These studies have highlighted a critical role for conformational change and the regulated formation of specific complexes that can either inhibit or stimulate apoptosis. In some cases, it is still not clear what distinguishes inhibitory from activating complexes, but the value of a structural understanding is highlighted by the success of recent structure-based drug discovery programs that have targeted these complexes.