From 1937 until 1999, West Nile virus (WNV) garnered scant medical attention as the cause of febrile illness and sporadic encephalitis in parts of Africa, Asia, and Europe. After the surprising detection of WNV in New York City in 1999, the virus has spread dramatically westward across the United States, southward into Central America and the Caribbean, and northward into Canada, resulting in the largest epidemics of neuroinvasive WNV disease ever reported. From 1999 to 2004, >7,000 neuroinvasive WNV disease cases were reported in the United States. In 2002, WNV transmission through blood transfusion and organ transplantation was described for the first time, intrauterine transmission was first documented, and possible transmission through breastfeeding was reported. This review highlights new information regarding the epidemiology and dynamics of WNV transmission, providing a new platform for further research into preventing and controlling WNV disease.