Neither the early nor the late steps in apoptosis have been defined biochemically. Several different signalling pathways have been implicated, and these are familiar from other signalling paradigms. In what way could they lead to cell death, when under the usual conditions they are involved in reversible activation events? A possible role for proteolysis is suggested, because the cleavage of a peptide bond is one of the few irreversible processes in cellular metabolism, and death, after all, is an irreversible outcome. In this review we discuss the calcium-dependent neutral protease calpain, a member of the papain family of cysteine proteases quite distinct from the ICE family. Calpain has been shown to play an essential role in several important examples of physiologic apoptosis. It seems to play its part after the various 'private' pathways have been invoked, but before the final common pathway.