West Nile virus (WNV) causes epidemics of febrile illness, meningitis, encephalitis, and flaccid paralysis. Since it was first detected in New York City in 1999, and through 2004, >16,000 WNV disease cases have been reported in the United States. Over the past 5 years, research on WNV disease has expanded rapidly. This review highlights new information regarding the virology, clinical manifestations, and pathology of WNV disease, which will provide a new platform for further research into diagnosis, treatment, and possible prevention of WNV through vaccination.