Since the first detection of West Nile virus in the Western Hemisphere in 1999, the virus has spread rapidly across the North American continent and as far south as Argentina. An unprecedented pattern of large annual epidemics of human neuroinvasive disease continues in North America, resulting in considerable public health impact. The high infection incidence in humans has resulted in non-mosquito transmission modes, such as through transfused blood and transplanted organs. West Nile virus incursion into Latin America and the Caribbean Islands has resulted in surprisingly low human, avian, and equine morbidity and mortality despite evidence that West Nile virus strains circulating in those regions are similar to those in North America.