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Although there are nearly 70 medically important Flaviviruses including Dengue and Zika, which cause over 100 million new infections each year with significant morbidity and mortality, vaccines are available for only a few of these viruses.  Furthermore, some of these vaccines require lengthy immunization courses or multiple boosters subjecting recipients to potential gaps in protection.  Therefore, non-vaccine based prophylactics and therapeutics could play a significant role in filling these gaps.  Unfortunately, despite over a decade of research only a few antiviral drug candidates have been advanced to clinical trials and for most of these the results have been disappointing.  Also, funding for antiviral research has been relatively scant in recent years.  Nevertheless, there are reasons for optimism.  There has been significant progress made in our understanding of Flaviviral infections, in the identification of promising drug targets and transmission abatement strategies, and in the establishment of protocols for drug discovery and for conducting human clinical safety and efficacy trials.  Multipronged efforts are currently ongoing to evaluate highly diverse approaches including (i) small molecule antivirals, (ii) virus-neutralizing and infection-blocking antibodies, (iii) viral receptor antagonists, (iv) infection-blocking oligonucleotides, and (v) strategies targeting the arthropod vectors.  A few areas of research that deserve special mention are phosphorodiamidate morpholino oligomers and peptide-linked phosphorodiamidate morpholino oligomers (PMOs/PPMOs), a class of infection-inhibiting, antisense oligonucleotides, which already have shown promising clinical safety and efficacy data, and the novel strategies being developed aimed at reducing viral transmission in endemic areas by targeting the arthropod vector-hosts, which have also shown promise.  The hope is that renewed commitment by government, academic, and private institutions will lead to licensed antiviral therapeutics, prophylactics, and other strategies aimed at preventing Flaviviral diseases in the not too distant future.