The detection of aberrant cells by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of 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 enhanced proliferation, survival, IFN-γ production and cytotoxicity toward tumours, in vitro. This was associated with increased JAK-STAT signalling in NK cells in which Cish was deleted. Cish^-/- mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity, uncovering CIS as a potent intracellular checkpoint in NK cell-mediated tumour immunity. In addition, subtle phenotypic changes in NK cells lacking Cish were observed in vivo at steady state, including an increase in terminally differentiated NK cells as well as increased expression of cell cycle markers. The changes observed in steady state Cish^-/- mice manifested in a lower activation threshold of their NK cells, evidenced by the redundancy of exogenous IL-15 to induce augmented production of inflammatory cytokines and cytotoxicity when stimulated ex vivo. These data suggest that Cish not only regulates NK cell responsiveness to IL-15, but may also play a role in maintaining an activation threshold, consequently regulating effector functions in vivo.