One of the lymphocyte effector molecules produced in vitro by antigen- and mitogen-stimulated lymphocytes is lymphotoxin, which has been proposed to be the cytodestructive mediator in cell-mediated immune reactions. Our in vitro findings suggest that lymphotoxin binds to sites on the plasma membrane of sensitive target cells, and this binding represents the earliest detectable effect in cell destruction induced by lymphotoxin. The kinetics of binding are rapid, and the affinity of lymphotoxin for binding sites is strong. Furthermore, cytodestruction can be localized, for lymphotoxin-coated cells cannot release lymphotoxin to affect adjacent 51Cr-labeled, noncoated cells in mixed cultures. This evidence suggests how a nonspecific soluble cytotoxin could cause highly specific localized tissue destruction.