The recent introduction of highly pathogenic strains of West Nile virus (WNV) into naïve populations in Europe, Israel, and the USA has resulted in a marked increase in both the number of reported cases and the severity of disease compared to previous outbreaks. The impact of the increased virulence of recently emerged strains of WNV is exacerbated by the fact that antiviral therapies and vaccines are not currently available for use in humans. A greater understanding of the viral and host factors involved in WNV-mediated neuropathology is necessary to facilitate the development of novel therapeutic approaches. This review summarizes the current state of knowledge of the role of the cell-intrinsic innate immune responses as well as the cell-mediated innate and adaptive immune responses in promoting the detection and clearance of WNV from the CNS.