Seasonal epidemics of West Nile virus (WNV) infection now occur throughout North America, causing clinical symptoms ranging from fever to encephalitis. There are no specific treatment options or licensed vaccines. Several classically developed vaccine candidates are being evaluated in clinical trials. However, questions of safety and/or immunogenicity may limit their usefulness. Mapping of human and murine antibody repertoires against the WNV envelope protein after WNV infection have revealed important insights into the protective immune response against the virus. This review will give an overview of vaccines under development and summarize current data on E-protein antigenicity that could aid in the design of next generation WNV vaccines.