Signal-dependent movement of proteins into and out of the nucleus through the importin superfamily of transporters is central to the replication of many viruses in infected cells, including RNA viruses such as the flavivirus Dengue virus (DENV). DENV non-structural protein 5 (NS5) traffics into and out of the host cell nucleus/nucleolus, being observed in the nucleus, although to differing extents, very early in infection in the case of all 4 DENV serotypes; with results from both reverse genetics and inhibitor studies indicating that this trafficking is critical to DENV infection. Knowledge of the transporters and targeting signals responsible for nuclear trafficking of NS5 has enabled inhibitors of DENV NS5 nuclear import to be identified using a novel screening/counterscreen approach. N-(4-hydroxyphenyl) retinamide (4-HPR) is of particular interest as a specific, non-toxic inhibitor able to protect against infection by all four serotypes of DENV, as well as the severe, antibody-enhanced form of DENV infection, in a lethal mouse model. Since 4-HPR can also inhibit DENV-related flaviviruses of medical significance such as West Nile Virus and Zika virus, it is of great interest for future commercialisation. Targeting nucleocytoplasmic trafficking of flavivirus proteins promises to be a powerful strategy to counter flaviviruses, for which the development of protective vaccines has thus far proven problematic.