West Nile virus (WNV) first appeared in the naive environment of the Western Hemisphere in 1999 in New York. Genetic analysis determined that the virus was introduced into the United States from the Mediterranean Basin. This review discusses the spread of the virus in 2001 from the initial focus in Queens, New York, to widespread activity in the eastern and midwestern United States. It concentrates on viral ecology, epizootiology, pathology, prediction, and prevention. Research questions to further our understanding of the transmission cycle of WNV are discussed, including host-preference studies, molecular confirmation of implicated mosquito vectors, and survival of WNV in the temperate environment of the United States. Comparisons are drawn with two other arboviruses enzootic in the United States, eastern equine encephalitis, and St. Louis encephalitis viruses. Although not recently introduced, these two viruses also demonstrated increased activity in the United States in 2001.