West Nile virus (WNV) is a mosquito-borne disease that emerged in North America where it caused in 2002 the largest arboviral meningoencephalitis outbreak ever recorded in this area. The viral variant responsible of this outbreak has been found to share 99.7% identity over the entire genome with the viral variant that caused the epizootic in Israel in 1998 and has been referred as “Isr98/NY99”. It has been shown to exhibit an increased neurovirulence in humans, as well as in experimental infections in different animal models. Mouse model has allowed to demonstrate the preferential infection of neurons within the central nervous system and to point out the genetic determinism of host susceptibility to WNV. In murine neural cell cultures, the selective infection of neurons was accompanied by physiopathological changes and a cytopathic effect, showing the direct effect of infection of neurons as one of the causes of WNV neuropathogenicity.