The increased spread of dengue fever and its more severe form, dengue hemorrhagic fever, have made the study of the mosquito-borne dengue viruses that cause these diseases a public health priority. Little is known about how or why the four different (serotypes 1-4) dengue viruses cause pathology in humans only, and there have been no animal models of disease to date. Therefore, there are no vaccines or antivirals to prevent or treat infection and mortality rates of dengue hemorrhagic fever patients can reach up to 20%. Cases occur mainly in tropical zones within developing countries worldwide, and control measures have been limited to the elimination of the mosquito vectors. Thus, it is imperative that we develop new methods of studying dengue virus pathogenicity. This article presents new approaches that may help us to understand dengue virus virulence and the specific mechanisms that lead to dengue fever and severe disease.