NK cell responses are determined by the balance of signals received through activating and inhibitory receptors. (A) NK cells sense healthy self-tissues through interactions between KIR and MHC-I molecules, which inhibit NK cell killing. (B) Malignant or virally infected cells upregulate stress ligands recognized through NK activating receptors, which can trigger killing. In the event that infected or transformed cells downregulate MHC-I, NK cells kill via missing-self response. (C) NK cells can induce apoptosis by releasing perforin and granzyme-containing granules or engaging death receptors on target cells; in addition, NK cells produce immune modulating cytokines and chemokines upon activation. (Inset) main activating and inhibitory receptors expressed by NK cells and their ligands, present on target cells. KIR-Long contain intracellular immunoreceptor tyrosine-based inhibitory motifs whereas KIR-Short lack intracellular immunoreceptor tyrosine-based inhibitory motifs and instead associate with membrane adapters with activating motifs.