The Japanese encephalitis virus and West Nile virus belong to the family Flaviviridae, genus Flavivirus; they have a similar transmission cycle, with birds serving as the natural vertebrate host and mosquitoes, primarily, Culex species, both serving as the enzootic vectors and infecting humans. These arboviruses have caused more human cases of severe neuroinvasive disease worldwide during the past decade than other mosquito-borne flaviviruses. The current data and concepts on the clinical manifestations, pathogenesis, diagnosis, and treatment of infections caused by West Nile virus and Japanese encephalitis virus, are considered. The need for developing innovative approaches to etiotropic therapy for West Nile fever and Japanese encephalitis is emphasized; these approaches should be based on the comprehensive insight and extensive studies of the pathogenesis of flaviviral infections.