West Nile virus (WNV) is a human pathogen which is rapidly expanding worldwide. It is a member of the Flavivirus genus and it is transmitted by mosquitos between its avian hosts and occasionally in mammalian hosts. In humans the infection is often asymptomatic, however, the most severe cases result in encephalitis or meningitis. Approximately 10% of cases of neuroinvasive disease are fatal. To date there is no effective human vaccine or effective antiviral therapy available to treat WNV infections. For this reason, research in this field is rapidly growing. In this article we will review the latest efforts in the design and development of novel WNV inhibitors from a medicinal chemistry point of view, highlighting challenges and opportunities for the researchers working in this field.