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Since its emergence in 1999 in America, West Nile virus (WNV) has become the leading cause of arboviral encephalitis in the United States. The infection is often asymptomatic but, when clinical manifestations occur, a broad range of symptoms is observed from flu-like symptoms to more serious neurological disorders that can sometimes lead to death. No treatment or vaccine is available for humans. Ongoing studies are trying to understand the host-virus dynamics that lead to the development of severe neurological symptoms in a minority of infected subjects. The amount of knowledge that was gained from parallel studies in animals and humans, comparing asymptomatic and symptomatic individuals, and using what was known of other Flaviviruses, will eventually translate to the development of potential therapeutic and prophylactic solutions. This review presents a synthesis of the most relevant findings concerning the immune response to WNV and its impact on disease outcome and gives an overview of the most promising therapeutic and prophylactic solutions.