The recent and continuing West Nile virus (WNV) epidemic in the US contributes to increased concerns about emerging virus infections, and in the current era, the potential use of pathogens such as virus of the Flaviviridae family in terrorism, infection with WNV is asymptomatic in many individuals, but can cause severe neurologic symptomatology and death in others. Additionally, there are increasing numbers of reports of persistent neurological symptom in individuals who survive WNV infection. Understanding the factors that lead to and/or protect from viral pathogenesis is crucial in this and similar infections. The role of the innate immune response, the first line of defense critical to initiating viral clearance and promoting a robust adaptive T cell response, has not been investigated in WNV. Furthermore, in addition to its protective role, it is possible that the innate immune response may contribute to pathology, especially in the brain. An understanding of this front-line innate response will allow insights into both immunity to WNV as well as potential therapies by manipulation of innate immunity. Here, we will focus our attention on natural killer (NK) cells and the innate immune response to WNV. We will utilize a mouse model involving infection with the WNV to study the mechanism of viral pathogenesis and the NK response.