Since the invasion of the mosquito-borne, West Nile virus (WNv) into North America in New York City (NYC) in 1999, the distribution of the virus has expanded throughout most of the continent during the ensuing years, causing mortality in hundreds of thousands of native and exotic birds and producing tens of thousands of equine and human cases. The initial outbreaks in the NYC area in 1999 were intense in local bird populations, with small outbreaks in humans and equines. Then, WNv spread north and south from this focal area during the next 2 years. The northward and southward sequence of dissemination continued as WNv began to encompass the remainder of the continent. Migrating birds are thought to be the one of the major contributors to the rapid dissemination of this mosquito-borne virus. The temporal and spatial pattern and rapidity of the continental spread of WNv, as detected by the national surveillance system, match the semi-annual migratory movements of hundreds of millions of North American birds. The subsequent dissemination of the virus to Canada, the Caribbean, Mexico, Central America, and now South America fits this method of spread as well. The strain of WNv introduced into the U.S. had increased virulence for North American birds, which quickly became apparent after its introduction and from the subsequent avian epizootics it caused. More than 200 species of birds experienced mortality, especially corvid species such as the American crow, blue jay, and several species of magpies, and recently the greater sage grouse. These species were particularly susceptible to this virulent strain of virus, as demonstrated in experimental studies and from dramatic die-offs during the summer virus transmission seasons. Bird mortality from WNv peaks during August-September at the height of the mosquito-transmission period but extends from April to November each year in some states. This mortality in crows and other corvid species was used as a sensitive sentinel system to detect the presence and movement of the virus through a public health reporting and laboratory testing national surveillance program. Mammal species were frequently infected, and some suffered mortality. The nationwide bird mortality from WNv infections was dramatic in North America during the last 7 years, but the actual impact of the mortality on bird populations is not known because of the insensitivity of national population data available on birds. Few regional declines in bird populations have been detected; however, the impact of WNv on local populations of crows and sage grouse has been observed in some localities. The geographical distribution of WNv activity is not continuous across local landscapes, and unexposed birds can then serve as a source to repopulate local impacted areas when overall populations are high. West Nile virus persists through the winter periods and reappears annually in the spring in temperate regions of the continent. The mechanisms responsible for this recrudescence are unique and largely unknown. Focusing on these overwintering locations with targeted mosquito control could suppress early season initiation of virus transmission and possibly prevent subsequent summer amplification. Integrated pest management aimed at controlling mosquito populations is currently the only effective approach to control this disease.