West Nile virus (WNV) is a neurotropic Flavivirus that was associated with sporadic outbreaks of meningoencephalitis in Africa and the Middle East until 1999, when a more virulent strain emerged in the US that caused thousands of infections among humans and horses, with reported fatality rates between 10 and 50%. Although the epidemiology of WNV is changing into a more endemic pattern in the US, and the incidence of neuroinvasive disease is decreasing, the long-term effects of resolved WNV infections in humans, characterized as persistent movement disorders and various functional disabilities, are a significant cause of morbidity. In addition, the horse industry is also negatively impacted by WNV infections, resulting in significant economic losses. Together with the fact that WNV is a potential bioterrorism agent, these factors suggest that there is a need for the development of a safe and effective vaccine against WNV. The increased understanding of WNV pathogenesis and correlates of protection enables the rational design of such a vaccine. Several experimental vaccines have been tested in preclinical models and some have undergone clinical trials. The challenges related to the development of cheaper, safer and more effective vaccines for use in both humans and horses are likely to be overcome by new technological developments in the field of vaccinology.