Natural killer (NK) cells are populations of lymphocytes that can be activated to mediate significant levels of cytotoxic activity and produce high levels of certain cytokines and chemokines. NK cells respond to and are important in defense against a number of different infectious agents. The first indications for this function came from the observations that virus-induced interferons alpha/beta (IFN-alpha and -beta) are potent inducers of NK cell-mediated cytotoxicity, and that NK cells are important contributors to innate defense against viral infections. In addition to IFN-alpha/beta, a wide range of other innate cytokines can mediate biological functions regulating the NK cell responses of cytotoxicity, proliferation, and gamma interferon (IFN-gamma) production. Certain, but not all, viral infections induce interleukin 12 (IL-12) to elicit NK cell IFN-gamma production and antiviral mechanisms. However, high levels of IFN-alpha/beta appear to be unique and/or uniquely dominant in the context of viral infections and act to regulate other innate responses, including induction of NK cell proliferation in vivo and overall negative regulation of IL-12 production. A detailed picture is developing of particular innate cytokines activating NK cell responses and their consorted effects in providing unique endogenous milieus promoting downstream adaptive responses, most beneficial in defense against viral infections.