Dengue virus (DENV) causes the most significant mosquito-borne viral disease in the world in terms of illness, death, and economic cost, due to the lack of an approved vaccine or antiviral. Infections with one of the four serotypes of DENV (DENV1-4) can result in diseases ranging from an acute, self-limiting febrile illness (dengue fever, DF) to life-threatening dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), yet exactly how viral and host factors contribute to the severe disease is unknown. Clinical observations have provided information on DENV pathogenesis, but the lack of an adequate animal model has hindered research on this important human pathogen. A mouse model is ideal for investigating host-pathogen interactions due to the immunological tools available, however, wild-type mice are resistant to DENV-induced disease. Therefore, the mouse models for DENV infection developed to date include infection of severely immunocompromised mice, non-physiologic routes of infection, and mouse-human chimeras, which all have their limitations. An inbred mouse model in which mice develop signs of human DENV-induced disease is needed to investigate the contribution of various immune components to protection and pathogenesis of DENV infections, and to test the efficacy of DENV vaccines and antivirals.