Natural killer (NK) cell immune responses are regulated by a balance of activating and inhibitory signals transmitted by cell surface receptors. Immunoreceptor tyrosine-based inhibition motifs in the cytoplasmic domains of inhibitory NK receptors recruit tyrosine or lipid phosphatases, which modulate the activation signals transmitted by receptors linked to the Syk and ZAP70 tyrosine kinases and phosphatidylinositol-3 kinases. In addition, recent studies of gene-deficient animals, in particular Syk and ZAP70 double-deficient mice, suggest that NK cells possess a robust and potentially redundant receptor system to ensure their development and function.