Natural killer cells express two distinct families of genes encoding receptors for polymorphic MHC class I molecules. Recent advances indicate that immunoreceptor tyrosine-based inhibitory motifs in the cytoplasmic domains of the killer cell inhibitory receptors and Ly-49 receptors recruit the SH2-containing protein tyrosine phosphatases, SHP-1 and SHP-2, resulting in inhibition of natural-killer- and T-cell-mediated cytotoxicity and cytokine secretion.