West Nile virus (WNV) is a small RNA virus. It was first isolated in the blood of a febrile woman in the West Nile district of Uganda in 1937. Although WNV has caused human disease in Africa and Europe since its identification, the first documented human infections occurred in the United States in 1999. Wild birds are the reservoir for WNV, and most transmission to humans occurs after the bite of an infected mosquito. In humans, 80% of infections are asymptomatic and nearly 20% cause a mild self-limiting illness called WNV fever. Less than 1% will develop central nervous system (CNS) infection, which manifests as meningitis, encephalitis, or acute flaccid paralysis. The case fatality rate for CNS infection is approximately 15%. Human vaccine is not available. Personal mosquito protection remains the best prevention, and treatment is supportive.