Dengue virus (DENV) causes dengue fever, a widely distributed endemic disease transmitted by mosquitoes. The complex interaction of DENV with the human immune system has complicated the development of an effective vaccine. This may be attributed, at least in part, to the lack of a suitable animal model capable to reproduce symptoms observed in humans. Mouse models are simple but usually rely on host-adapted virus strains or immunodeficient mouse lineages. Recent evidences indicated that some natural DENV strains are capable to infect immunocompetent mice. In addition, humanized mouse lineages can more faithfully reproduce some of the symptoms observed in humans. Such experimental models are valuable tools for the study of DENV biology.