Molecular evolution studies suggest that dengue virus (DENV) evolved 1000 years ago and entered a sustained human–mosquito cycle between 125 and 320 years ago. While it is unlikely that DENV would be used as a biothreat agent, DENV has emerged since World War II as the most important mosquito-borne viral pathogen infecting an estimated 100 million persons each year. Infection with any of the four DENV serotypes (DENV-1, 2, 3, and 4) can be inapparent, result in classic dengue fever with high fever, headache, eye pain and muscle ache, or progress at the time of defervescence to dengue hemorrhagic fever (DHF) characterized by hemorrhagic manifestations and plasma leakage that can lead to shock and death. The immunopathological mechanisms by which DENV causes the clinical features of DHF are intricate and include aberrant humoral and cellular immune responses. Previous DENV infections may predispose to more severe disease by the induction of enhancing antibody and cross-reactive T cells. Treatment is supportive relying upon careful fluid management which can be lifesaving.