Cytotoxic T lymphocytes and natural killer cells together comprise the means by which the immune system detects and rids higher organisms of virus-infected or transformed cells. Although differing considerably in the way they detect foreign or mutated antigens, these cells utilize highly analogous mechanisms for inducing target cell death. Both types of effector lymphocytes utilize two principal contact-dependent cytolytic mechanisms. The first of these, the granule exocytosis mechanism, depends on the synergy of a calcium-dependent pore-forming protein, perforin, and a battery of proteases (granzymes), and it results in penetration by effector molecules into the target cell cytoplasm and nucleus. The second, which requires binding of FasL (CD95L) on the effector cell with trimeric Fas (CD95) molecules on receptive target cells, is calcium independent and functions by generating a death signal at the inner leaflet of the target cell membrane. Exciting recent developments have indicated that both cytolytic mechanisms impinge on an endogenous signaling pathway that is strongly conserved in species as diverse as helminths and humans and dictates the death or survival of all cells.