Natural killer (NK) cells have evolved to detect and kill aberrant cells. NK cell function is governed by the cytokine interleukin (IL)-15 and the detection of foreign and self-ligands, which together generate an integrated intracellular signal cascade. There has been a great deal of interest in understanding the inhibitory signals that curb NK cell responses, yet we still do not understand how IL-15 signalling is switched off. The Suppressor of cytokine signalling (SOCS) proteins are induced in response to JAK/STAT activation and act to limit the extent of cytokine receptor signalling. We have identified CIS (Cytokine-inducible SH2-containing protein; Cish gene) as the critical SOCS protein regulating IL-15 signalling in NK cells. Cish was rapidly induced in response to IL-15 and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by superior proliferation, survival, IFN-γ production and cytotoxicity towards tumours. Cish–/– mice were resistant to experimental melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. This study has uncovered a potent checkpoint in NK cell-mediated tumour immunity.