Natural killer (NK) cells contribute to the immune defense against cancer and viruses. Tumor cells and infected cells that downregulate the HLA class I antigen expression are targets for NK cell responses because NK cell activation is controlled by a repertoire of inhibitory receptors with different HLA class I specificities. The clonal distribution of these inhibitory receptors permits NK cell recognition of target cells that have lost expression of a single HLA-B or HLA-C allotype. Several activation receptors on NK cells have been identified that contribute to tumor cell recognition. One such receptor, NKG2D, is expressed by all NK cells and binds to inducible ligands on tumor cells.