Since its discovery in Uganda (1937), West Nile (WN) fever historically remained confined in Africa and Middle East with sporadic incursions in Southern Europe. However, it has expanded in the last decades, and is now one of the most widespread arboviruses in the world. Nowadays WN remains present over six continents. The disease is produced by a virus (WNV, genus Flavivirus) and transmitted by mosquitoes among susceptible hosts, usually birds. The virus can also affect dead-end hosts, like humans and equines. The identification of the drivers for WN emergence and spread is difficult. At local scale, WN transmission cycle can occur through different ecosystems with involvement of different species of vectors and hosts. High viral genetic variation and wide range of vectors and hosts makes WN a complex arthropod-borne disease. Recently, up to nine different WNV lineages have been proposed. WNV has been detected in more than 60 mosquito species in 11 genera. However species in the Culex genus are considered the main WNV vectors worldwide. Major amplifying hosts are birds, with more than 300 species of birds supporting infection. Mammals are generally considered as dead-end hosts as they are not efficient WNV amplifiers. Nevertheless, multiple mammalian species, amphibian and reptiles are susceptible to WNV infection. WNV emerged in the New World in New York, 1999. Since then the virus provoked in the USA the major WNV epidemics ever recorded globally. Disease burden was high, causing significant morbidity and mortality in birds, horses and humans. The disease further spread northward (Canada) and southward. The southern spread of WNV into the Caribbean, Central and South America was apparently silent. In contrast to USA and Canada, WNV has caused no or very limited health impact on animal and human populations in the Caribbean. The apparent absence of bird mortality and clinical manifestations among humans or equines makes difficult to track WNV spread in the region.