In North America, the geographic distribution, ecology, and vectorial capacity of a diverse assemblage of mosquito species belonging to the genus Culex determine patterns of West Nile virus transmission and disease risk. East of the Mississippi River, mostly ornithophagic Culex pipiens L. complex mosquitoes drive intense enzootic transmission with relatively small numbers of human cases. Westward, the presence of highly competent Culex tarsalis (Coquillett) under arid climate and hot summers defines the regions with the highest human risk. West Nile virus human risk distribution is not uniform geographically or temporally within all regions. Notable geographic ‘hotspots' persist with occasional severe outbreaks. Despite two decades of comprehensive research, several questions remain unresolved, such as the role of non-Culex bridge vectors, which are not involved in the enzootic cycle, but may be involved in virus transmission to humans. The absence of bridge vectors also may help to explain the frequent lack of West Nile virus ‘spillover’ into human populations despite very intense enzootic amplification in the eastern United States. This article examines vectorial capacity and the eco-epidemiology of West Nile virus mosquito vectors in four geographic regions of North America and presents some of the unresolved questions.