Very little is known about the receptors and target molecules involved in natural killer (NK) cell activity. Here we present a model system in which interleukin-2-activated killing by NK cells depends on the intercellular adhesion molecule ICAM-2 and is regulated by the distribution of ICAM-2. The level of ICAM-2 expression in NK-sensitive and resistant cells is similar, but in sensitive cells ICAM-2 is concentrated into bud-like cellular projections known as uropods, whereas in resistant cells it is evenly distributed. The cytoskeletal-membrane linker protein ezrin is also localized in uropods. Transfection of human ezrin into NK-resistant cells induces uropods formation, redistribution of ICAM-2 and ezrin, and sensitizes target cells to interleukin-2-activated killing. These results reveal a new mechanism of target-cell recognition: cytotoxic cells recognize adhesion molecules that are already present on normal cells, but in diseased cells are concentrated into a biologically active cell-surface region by cytoskeletal reorganization. The results also highlight the importance of cytoskeletal interactions in the regulation of ICAM-2-mediated adhesive phenomena.