NK cells are known as innate immune cells and mediate cytotoxicity against cells infected with pathogens early following infection. NK cells are also a source of cytokines such as IFNc and TNFa and are therefore instrumental in activating the adaptive arm of the immune system. Although NK cells possess various activating and inhibitory receptors, they lack classical antigen recognizing receptors. Consequently, NK cells are unable to mount antigen specific immune responses, expand in response to Ags and display immunological memory. A few recent records have challenged the notion that NK cells lack the capability to elicit antigen specific immune responses that may lead to the host acquiring NK cell memory. Existence of memory in the invertebrate innate immune system has been shown using a copepod parasite infection model. Furthermore, recent records have indicated the existence of a subset of NK cells that remember activation by cytokines, encounters with chemical haptens and mouse cytomegalovirus infection. These subsets of NK cells were phenotypically similar cells, but distinct because they lack constitutive expression of IFNc and granzyme B. However, this subset of NK cells could be activated to produce higher IFNc and kill target cells like na?ve NK cells. These Ly49H+ NK cells could undergo expansion, contraction, memory maintenance and secondary recall response following recognition of the MCMV protein m157. The duration of memory response displayed by NK cells appears to be varied. Memory response following the application of chemical haptens appears to persist for about a month, whereas that recorded against MCMV persisted for several months. It has also been observed that NK cells that are activated by DCs provide protection up to one year against B16 melanoma in a mouse model. Interestingly, this long-term protection mediated by the NK cells following DC treatment relied on CD4+ T cells and was abrogated following elimination of IFNc. In agreement with the findings of the later study, following human immunization against rabies, NK cells acquired the capability of higher IFNc production and degranulation upon re-exposure for up to 4 months. This long term Ag specific proliferation and enhanced NK cell activity has been shown to be dependent on IL-2 signaling from memory CD4+ T cells. A high percentage of NK cells possess the Ly49H+ receptor that specifically recognizes MCMV Ag, m157, which facilitated the characterization of memory NK cells generated against MCMV. It is not known whether NK cells can display memory responses against any other viral infections and if they do, whether it is B- and T- lymphocyte independent since it has been shown that NK cell mediated protection induced by DCs is dependent on CD4+ T cells and increased proliferation and activity in rabies Ag re-exposed human NK cells depend on IL-2 signaling derived from memory CD4 T-cells. Here, we first investigated whether NK cells are able to remember and respond following re-exposure to another viral infection other than MCMV. We then examined if this can occur in the absence of T- and B-lymphocytes, For this end, we used a well-established mouse model of genital herpes simplex virus type-2 infection in which it is known that NK cells are important for protection.