Since its introduction to North America in 1999, West Nile virus, an arthropod-borne flavivirus, has become the most significant cause of epidemic encephalitis in the western hemisphere. While most human infections with the virus are asymptomatic and the majority of symptomatic persons experience febrile illness, severe neurologic manifestations, including meningitis, encephalitis, and poliomyelitis may be seen. This review summarizes the virology, epidemiology and pathogenesis of human infection with West Nile virus, and details recent advances in our understanding of the pathophysiology and various clinical manifestations of infection.