The suppression of apoptosis is essential to the propagation of viruses, and to the control of development and homeostasis in insects and mammals. The central components of all apoptotic pathways are proteases of the caspase family. Therefore, it is not surprising that the processes of natural selection, as well as pharmaceutical chemists, have designed compounds that directly target caspase activity in attempts to regulate apoptosis. The mechanisms used by highly specialized naturally occurring caspase inhibitors (both host and viral) have remained obscure for some time. However, recently there has been significant progress in this field, particularly because of the structural elucidation of the complexes between caspases and an endogenous inhibitor (XIAP) and a viral inhibitor (p35). This article reviews the newly defined molecular basis for the regulation of the caspases by viral and endogenous inhibitors.