Natural killer (NK) cells and interleukin-2 activated NK cells, termed lymphokine-activated killer (LAK) cells, can lyse tumor cells without restriction by the MHC complex. The cytotoxic activity of these cells is subject to regulation by nonlymphoid cells in vitro. Interaction of NK cells with red blood cells (RBC) increases NK cytotoxicity. Interaction with polymorphonuclear neutrophils (PMN) suppresses LAK development and also inhibits NK- and LAK-mediated cytotoxicity at the effector cell phase. Exposure to tumor necrosis factor-alpha greatly enhances the inhibitory effect of PMN at the effector cell phase. Depending on their states of activation and differentiation, monocytes have the capacity to either enhance or suppress LAK induction. In contrast, macrophages derived from the lung are potent inhibitors of NK and LAK activity at both the induction and effector cell phases. Several cytokines are secreted by monocytes and macrophages and these include both suppressive and enhansive factors of cytotoxic function. Platelets are also capable of releasing suppressive factors. NK cells are believed to be involved in host surveillance of tumors, control of microbial infections and regulation of hematopoiesis. Regulation of NK cells by nonlymphoid cells and their products likely provides an in vivo mechanism for locally regulating NK function.