Dengue virus (DENV) causes the most prevalent arbovirus illness worldwide and is responsible for many debilitating epidemics. The four circulating DENV serotypes infect humans and can cause asymptomatic, mild, moderate, or severe Dengue. Because of the global morbidity and mortality due to Dengue, deployment of a safe and effective tetravalent vaccine has been a high priority, and to date, a partially realized goal. The study of pathogenesis and development of DENV therapeutics and vaccines has been limited by few animal models that recapitulate key features of human disease. Over the past two decades, mouse models of DENV infection have evolved with increasing success. Here, we review the utilization and limitations of mice for studying DENV pathogenesis and evaluating countermeasures.