There are currently no licensed antivirals available for the treatment of dengue virus (DENV), which causes significant morbidity and mortality throughout tropical areas of the world and is now encroaching on the southern United States. Recent improvements in existing animal models and cell culture systems have been very important in elucidating the mechanisms of DENV pathogenesis in humans, including the identification of potential viral and host proteins that might be targeted for the treatment of DENV infection. The AG129 mouse model is a major advance in the development of antiviral and vaccine candidates for clinical use. It allows for testing of potential therapeutics in a relevant system that exhibits some aspects of disease that are similar to those observed in humans. This review focuses on recent developments in the AG129 mouse model and discusses compounds that have been found to be active in available cell and animal model systems within the past year.