West Nile virus (WNV) has historically been considered to be among the least virulent of the Japanese serogroup viruses of the family Flaviviridae, genus Flavivirus. However, recent epidemics associated with severe and fatal neuroinvasive disease have changed that perception. The emergence of a virus subtype with greater epidemic potential and virulence in the early 1990s facilitated the geographic expansion and westward spread of WNV; in 1999, it first appeared in the western hemisphere. Because of the broad host and vector range, the virus has become established in much of the region, and there is little chance that it will be eliminated. Transmission is difficult to predict and even more difficult to prevent and control. The cost-effectiveness of human WNV vaccines is uncertain. The building of laboratory diagnostic, epidemiologic, and vector-control capacity in WNV-enzootic countries is critical to the development of effective prevention and control strategies for WNV infection, as well as for other potential emerging vectorborne viral diseases.