Many flaviviruses cause important and serious human diseases, including yellow fever, West Nile, Japanese encephalitis and tick-borne encephalitis viruses. Two further flaviviruses, the closely related dengue and Zika virus, have emerged as significant threats to global health with their potential to inflict severe disease to millions of people. Here, we look at some of the molecular similarities and differences between these two emerging diseases, as this is key to the development of novel preventions and therapeutics.