NK cell cytotoxicity, IFN-γ expression, proliferation, and accumulation are rapidly induced after murine CMV infections. Under these conditions, the responses were shown to be elicited in overlapping populations. Nevertheless, there were distinct signaling molecule requirements for induction of functions within the subsets. IL-12/STAT4 was critical for NK cell IFN-γ expression, whereas IFN-αβ/STAT1 were required for induction of cytotoxicity. The accumulation/survival of proliferating NK cells was STAT4-independent but required IFN-αβ/STAT1 induction of IL-15. Taken together, the results define the coordinated interactions between the cytokines IFN-αβ, IL-12, and IL-15 for activation of protective NK cell responses during viral infections, and emphasize these factors’ nonredundant functions under in vivo physiological conditions.