Abstract: West Nile virus, first isolated in 1937, is among the earliest arthropod-borne viruses discovered by humans. Its broad geographical distribution, not uncommon infection of humans, transmission by mosquitoes, and association with wild birds as enzootic hosts were well documented by the mid-1960s. However, West Nile virus was not considered to be a significant human pathogen because most infections appeared to result in asymptomatic or only mild febrile disease. Several epidemics had been documented prior to 1996, some involving hundreds to thousands of cases in mostly rural populations, but only a few cases of severe neurological disease had been reported. The occurrence between 1996 and 1999 of three major epidemics, in southern Romania, the Volga delta in southern Russia, and the northeastern United States, involving hundreds of cases of severe neurological disease and fatal infections was totally unexpected. These were the first epidemics reported in large urban populations. A significant factor that appeared in common to all three outbreaks was the apparent involvement of the common house mosquito, Culex pipiens, as a vector. This species had not previously been implicated as important in the transmission of West Nile virus. In addition the epidemic in the northeastern United States was unusual in the association of West Nile virus infection with fatal disease of birds, suggesting a change in the virulence of the virus toward this host. Understanding the risk factors that contributed to these three urban epidemics is important for minimizing the potential for future occurrences. This review will attempt to compare observations on the biology of West Nile virus made over about 60 years prior to the recent epidemics to observations made in association with these urban epidemics.