AbstractThere is evidence that natural cytotoxic (NC) cells are in the T cell lineage. To lyse targets, cytotoxic T cells (TK) must recognize any of the myriad antigens plus syngeneic major histocompatibility complex (MHC) determinants. In spite of the evidence which indicates TKand NC are in the same lineage, NC cells can recognize few determinants (perhaps only one) and do not require recognition of MHC determinants.In addition to differences in the requirement for target recognition, in this report we show that TKcells and NC cells also use different lytic mechanisms to lyse the same targets. NC effectors initiate a lytic mechanism in NC‐sensitive and NC‐resistant targets. This lytic mechanism requires approximately 4 h before target lysis is apparent in NC‐sensitive targets; it is inactivated by a protein synthesis‐dependent counterlytic mechanism in NC‐resistant targets. In contrast the TKlytic mechanism causes a rapid release of51Cr from both NC‐sensitive and NC‐resistant targets and is not inhibited by the NC counterlytic mechanism present in NC‐resistant cells. These findings lead to the conclusion that the mechanism used by NC cells to lyse targets is fundamentally different from that