Flaviviruses, such as the dengue virus and the West Nile virus, are emerging arthropod-borne viruses that represent an immense global health problem. Considerable progress has been made in understanding flavivirus structure and replication strategies, but only now are the complex molecular interactions between the virus and host cell starting to be unraveled. In this Review, we discuss the ongoing efforts toward elucidating the molecular mechanisms that allow flaviviruses to manipulate host cell functions for successful infection. We draw attention to the importance of these studies in defining the pathogenesis of flaviviral diseases.