Macrophage inflammatory protein 1α (MIP-1α) promotes natural killer (NK) cell inflammation in livers during murine cytomegalovirus (MCMV) infections, and NK cell–produced interferon γ (IFN-γ) contributes to defense against MCMV infections. A specific role for local NK cell IFN-γ production, however, has not been established. The importance of MIP-1α and NK cell–produced IFN-γ in shaping endogenous immune responses and defense in different compartments was examined. MIP-1α deficiency profoundly decreased resistance to MCMV and was associated with dramatically reduced NK cell accumulation and IFN-γ production in liver. MIP-1α–independent IFN-γ responses were observed in serum and spleen, and infection-induced elevations in blood NK cell populations occurred in absence of the factor, but peak liver expression of another chemokine, the monokine induced by IFN-γ (Mig), depended upon presence of MIP-1α, NK cells, and IFN-γ. The Mig response was also important for viral resistance. Thus, serum cytokine responses are insufficient; MIP-1α is critical for NK cell migration and IFN-γ delivery to mediate protection; and Mig induction in tissues is a downstream protective response resulting from the process. These results define a critical chemokine-to-cytokine-to-chemokine cascade required for defense during a viral infection establishing itself in tissues.