Since its entry into North America in 1999, West Nile virus has spread throughout the USA and Canada, and now annually causes a clinical spectrum of human disease ranging from a self-limiting acute febrile illness to potentially lethal encephalitis. Although no therapy is currently approved for use in humans, several strategies are being pursued to develop effective prophylaxis and treatments. This review describes the epidemiology, clinical presentation and pathogenesis of West Nile virus infection, and highlights recent progress towards an effective therapy.