In 1999, an epidemic of West Nile virus (WNV) encephalitis occurred in New York City (NYC) and 2 surrounding New York counties. Simultaneously, an epizootic among American crows and other bird species occurred in 4 states. Indigenous transmission of WNV had never been documented in the western hemisphere until this epidemic. In 2000, the epizootic expanded to 12 states and the District of Columbia, and the epidemic continued in NYC, 5 New Jersey counties, and 1 Connecticut county. In addition to these outbreaks, several large epidemics of WNV have occurred in other regions of the world where this disease was absent or rare >5 years ago. Many of the WNV strains isolated during recent outbreaks demonstrate an extremely high degree of homology that strongly suggests widespread circulation of potentially epidemic strains of WNV. The high rates of severe neurologic illness and death among humans, horses, and birds in these outbreaks are unprecedented and unexplained. We review the current status of WNV in the United States.