Cytotoxic effector lymphocytes were produced by stimulation of human peripheral blood or mouse spleen lymphocytes with PPD, PHA or PWM in vitro. The specificity of the lymphocyte target cell interaction was studied in vitro. The specificity of the lymphocyte target cell interaction was studied by adsorption of effector cells on various target cell monolayers. The cytotoxic activity of human lymphocytes against 51Cr-labeled human or monkey target cells was reduced by prior incubation on primate monolayers while it was much less affected by incubation on rodent monolayers. Conversely the cytotoxicity of mouse lymphocytes against mouse L cells was strongly reduced by absorption on mouse or rat monolayers but significantly less by that on human monolayers. This suggests that this species-specific cytotoxicity reflects recognition by activated lymphocytes of some common surface structures present only on cells of the species of the effector cell donor, or on cells from phylogenetically closely related species. Lymphocyte-mediated cytotoxicity against xenogeneic target cells was studied after stimulation with PWM. The capacity of human lymphocytes to kill 51Cr-labeled mouse cells was reduced by adsorption on either rodent or primate monolayers. Conversely, prior incubation of mouse lymphocytes on either human or mouse monolayers led to inhibition of 51Cr release from labeled Chang cells. These results suggest that the mitogen-activated effector cells which are cytotoxic for more distantly related xenogeneic target cells have receptors for structures which are common for these cells and for target cells of the species of the lymphocyte donors.