Emerging flaviviral pathogens represent a significant current and projected global health crisis. Dengue virus (DENV) is the leading disease-causing arbovirus in the world, with over 390 million infections annually, resulting in more than 500,000 severe cases requiring hospitalization. Adding to this burden, the recent global spread of the related Zika virus (ZIKV) has caught governments and aid agencies by surprise and resulted in the WHO declaration of a global health emergency. The co-circulation of related flaviviruses poses significant complications for accurate diagnosis as well as vaccine design. However, similarities between flaviviruses also offers the potential for the development of future treatments and vaccines that could offer broad protection against these important human pathogens. All flavivirus genomes encode a protein known as non-structural protein 1 (NS1). We recently revealed that DENV NS1 acts like a viral toxin, driving the induction of inflammatory cytokines and directly damaging the endothelial barrier. In this talk I describe progress we have made towards new therapies that target NS1, and the potential for NS1 as a broad spectrum antiviral target.