NK cells contribute to innate defense during certain viral infections, but the mechanisms for their regulation and delivery of antiviral effects are incompletely understood. A second NK cell population, from within T cell populations — NKT cells — has a unique potential to initiate cellular effector mechanisms, including those delivered by NK cells, provided that the antigen for their restricted TCR is induced during infection. If elicited, particular innate cytokine responses promote activation of NK cell cytotoxicity or IFN-γ production. These responses can contribute to defense by mediating antiviral and/or immunoregulatory effects. Roles of positive or negative receptors for target cells in protection against viruses are less clear. Exciting new data indicate that, in at least one system, NK cell receptors that positively signal for activation participate in the recruitment of these cells into antiviral defense mechanisms. Other recent evidence suggests that NKT cells may be important for protection during one viral infection and may be artificially activated by delivery of antigen to promote antiviral defense. Taken together, these recent advances in the characterization of the NK and NKT cell responses are filling in the details of the complex and critical events taking place, at the earliest times after challenge, to promote resistance to viruses.