The characteristics of cytotoxic T lymphocyte (CTL) and natural killer (NK) cell recognition of and binding to target cells (conjugate formation), and the precise mechanism(s) by which the target cells are triggered to undergo apoptotic cell lysis are now being deciphered at the cellular and molecular levels. Involvement of a multitude of cell surface molecules, in addition to T cell receptor (TCR)-major histocompatibility (MHC)-peptide complexes, in the binding and signalling for lymphocyte-mediated lysis has been demonstrated. Two proposed mechanisms of lymphotoxicity currently appear to be valid: (i) a membranolytic one initiated by the formation of pores in target cell membranes by secreted molecules of lymphocyte origin, such as perforin and granzymes, and (ii) a nonsecretory one initiated by receptor-mediated triggering of apoptosis-inducing target cell surface molecules, but not involving the secretion of pore-forming agents and granzymes. Perforin and granzymes are probably involved in lymphocyte activation and are likely mediators of the membranolytic pathway of lymphotoxicity. Existence of the nonsecretory and receptor-triggered lytic mechanism was indicated by (i) the prelytic fragmentation of the target cell's DNA, which precedes release of intracellular (51Cr-labeled) components, (ii) the demonstration of cytolytic effector cells that are either devoid of or express background levels of lytic granules and perforin, and (iii) the observation that some CTL lyse target cells under conditions at which perforin and granzymes are neither secreted nor lytic, e.g. [Ca2+]o < 1 micromolar. These two mechanisms are not mutually exclusive and are probably used by different types of effector cells or by the same effector cells at different stages of differentiation. In fact, recent perforin gene knock-out experiments support the existence of both.