In the late summer of 1999, the first known cases of West Nile virus infection in the Western Hemisphere were recorded in New York City. These first cases were the hallmarks of an outbreak of West Nile virus infection that resulted in 7 deaths among 62 confirmed cases and an estimated 8200 asymptomatic to mild infections among residents and visitors in Queens, New York. This article reviews West Nile virus and its spread in the United States since its introduction in 1999.