Dendritic cells (DCs) regulate various aspects of innate immunity, including natural killer (NK) cell function. Here we define the mechanisms involved in DC -NK cell interactions during viral infection. NK cells were efficiently activated by murine cytomegalovirus (MCMV) -infected CD11b+ DCs. NK cell cytotoxicity required interferon-α and interactions between the NKG2D activating receptor and NKG2D ligand, whereas the production of interferon-γ by NK cells relied mainly on DC-derived interleukin 18. Although Toll-like receptor 9 contributes to antiviral immunity, we found that signaling pathways independent of Toll-like receptor 9 were important in generating immune responses to MCMV, including the production of interferon-α and the induction of NK cell cytotoxicity. Notably, adoptive transfer of MCMV-activated CD11b+ DCs resulted in improved control of MCMV infection, indicating that these cells participate in controlling viral replication in vivo.