Significance Dengue affects approximately one-half of the world’s population. While it causes regular and cyclical outbreaks throughout the tropical world, the molecular mechanisms that determine its epidemic potential remain poorly defined. The present work provides insight into the molecular determinants of epidemiologic fitness, which is critical for surveillance to identify dengue virus strains with a potential to cause outbreaks. This will allow for better implementation of control measures to intercept impending outbreaks before many lives are affected.