Dengue fever is an emerging mosquito-borne flaviviral disease that threatens 2.5 billion people worldwide. No clinically approved vaccine and antiviral therapy are currently available to prevent or treat dengue virus (DENV) infection. Vertebrate animals other than primates are not normally infectable with DENV; however, a small animal dengue infection model would greatly facilitate the development of a vaccine or an antiviral therapy. To this end, a rodent model for DENV infection has been established in IFN-α/β and IFN-γ receptor-deficient (AG129) mice. This chapter describes the protocol for the DENV infection model in AG129 mice and testing of antiviral compounds by oral gavage or parenteral injection.