WNV is a flavivirus with widespread distribution throughout Africa, the Mediterranean, and Eurasia. Originally isolated from human blood in Uganda, Africa, in 1937, WN virus is maintained in nature primarily by transmission between birds by mosquitoes. WN virus is endemic year-round in parts of Africa, the Middle East, and Asia. There is occasional seasonal spread, coincident with migrating birds and mosquito activity, into more temperate regions such as France, Italy, and eastern Europe. Recent outbreaks have included a large one in Romania during 1996 - 1997, and one in Italy in 1998 prior to which there had never been any clinically or serologically confirmed cases in the country.

In 1999 an outbreak of West Nile Virus (lineage 1) encephalitis first occurred in New York City in late August and has since been identified throughout the East and Gulf states and is beginning to spread west. Because of the ease of spread between birds by mosquitoes it is believed this disease will spread through all of the US in the next 5 to 10 years if not quicker. This was the first occurrence of West Nile (WN) virus in the Western Hemisphere. Because of similarities to an outbreak in Israel the year before it is believed it came into the city by a mosquito in an airplane from Israel. In the fall of that year, WN virus was identified as a cause of encephalitis in 25 horses in two New York counties.

During the 2000 transmission season, 60 equids in seven northeastern states were confirmed cases of WN viral encephalitis.2 In 2001, the virus was identified in most states in the eastern half of the United States, and 738 clinically apparent equine infections occurred. Although 20 states had at least one confirmed case of equine WN encephalitis in 2001, the epizootic was dominated by Florida and Georgia; cases in those states accounted for more than 75% of the total.

By the fall of 2002 the infection had spread to just about every state east of the Rockies and rapidly being detected in new states with over 2000 horses positively identified as having become infected. Though California had a case in 2002 it is thought to be a single event at this time, possibly a already infected mosquito transported to the state. The virus rapid spread surprised everyone and appears to be do to several factors, the most important being how efficient a host the Culex tarsalis mosquito is. WNV will infect other species of mosquitos. Typically the West Nile virus does not cause a high mortality in crows. The fact that so many crows have been affected in this outbreak could be due to exposure of a native bird population or a new, more virulent stain. However recent work seems to contradict this and perhaps a naive population is more susceptible do to lack of immune resistance.

WNV lineage 2, the first WNV lineage to be isolated, was believed to be restricted to sub-Saharan Africa causing a relatively mild fever in humans. However, in 2004, an investigation in Hungary of a case of encephalitis in a wild goshawk (Accipiter gentiles) resulted in the isolation of WNV lineage 2. During the summer of 2004, and in subsequent years, the virus appeared to spread locally throughout Hungary and into neighboring Austria. Subsequently, WNV lineage 2 emerged in Greece in 2010 and in Italy in 2011, involving outbreaks on the Italian mainland and Sardinia. Further spread through the Balkan countries is also suspected. Whole genome sequencing has confirmed that the virus responsible for the outbreaks in Greece and Italy was almost identical to that isolated in Hungary. However, unlike the outbreaks in Hungary, the burden of disease in Mediterranean countries has fallen upon the human population with numerous cases of West Nile fever and a relatively higher mortality rate than in previous outbreaks. Experiments and observations have shown the lineage 2 type is very pathogenic to the horse.