West Nile (WN) virus first appeared in the Southeastern USA during the summer of 2001 when 21 human cases were reported in the region. Since 2001, sporadic transmission of WN virus has been reported throughout the Southeast. A total of 829 human WN cases were reported in the region between 2001 and 2004. The majority of these cases (318, 38%) were from Mississippi. The movement of WN virus through Florida is used in this presentation as an example of range expansion by an exotic virus. To date, the Southeast has failed to report a major WN epidemic comparable to those already observed in the Midwest, High Plains, and Southwest regions of the USA between 2002 and 2004. This is likely because of the ecology and natural history of WN virus in the Southeast where Culex quinquefasciatus and Culex nigripalpus serve as major amplification and transmission vectors.