Natural killer (NK) cells are naturally circulating innate lymphoid cells that protect against tumor initiation and metastasis and contribute to immunopathology during inflammation. The signals that prime NK cells are not completely understood, and, although the importance of IFN type I is well recognized, the role of type III IFN is comparatively very poorly studied. IL-28R–deficient mice were resistant to LPS and cecal ligation puncture-induced septic shock, and hallmark cytokines in these disease models were dysregulated in the absence of IL-28R. IL-28R–deficient mice were more sensitive to experimental tumor metastasis and carcinogen-induced tumor formation than WT mice, and additional blockade of interferon alpha/beta receptor 1 (IFNAR1), but not IFN-γ, further enhanced metastasis and tumor development. IL-28R–deficient mice were also more susceptible to growth of the NK cell-sensitive lymphoma, RMAs. Specific loss of IL-28R in NK cells transferred into lymphocyte-deficient mice resulted in reduced LPS-induced IFN-γ levels and enhanced tumor metastasis. Therefore, by using IL-28R–deficient mice, which are unable to signal type III IFN-λ, we demonstrate for the first time, to our knowledge, the ability of IFN-λ to directly regulate NK cell effector functions in vivo, alone and in the context of IFN-αβ.