Although the role of natural killer (NK) cells in defense against certain viral infections has been appreciated for a number of years, characterization of the virus-induced endogenous mechanisms regulating NK cell responses and functions has been limited to interferon (IFN)-alpha/beta-mediated activation of NK cell cytotoxicity. Studies of experimental infections have demonstrated that virus-induced NK cells undergo blastogenesis and can be activated to produce IFN-gamma. Recent work has shown that some, but not all, viral infections induce IL-12, the expression of which results in NK cell IFN-gamma production, and that NK cell IFN-gamma production contributes to an antiviral state. IL-12 expression can be regulated by IFN-alpha/beta, and endogenous IFN-alpha/beta is responsible for the lack of IL-12 during viral infections that fail to elicit detectable production of this factor. Once T cell responses are activated, additional mechanisms are in place to turn off NK cell functions. These studies demonstrate that viral infections elicit unique mechanisms for regulating NK cell responses, and suggest that the host requires tight control of NK cells under these conditions.