Here we summarized our findings in the mouse model of the events that lead to dengue hemorrhage. Immunocompetent mice inoculated intradermally with DENV-2 strain 16681 develop hemorrhage locally or systemically. The incidence and the severity of hemorrhage development are dependent on the size of viral inoculum. The hemorrhage mice exhibit severe thrombocytopenia, prolonged bleeding time, and increased numbers of circulating endothelial cells. In the hemorrhage tissues, there is endothelial damage accompanied by infiltrating macrophages that secret TNF-alpha. The endothelial cells express iNOS and peroxynitrite and undergo apoptosis, indicating RNS and ROS production may lead to cell death. By using mice deficient in iNOS and phox47 and apocynin, we demonstrated that RNS and ROS are important to hemorrhage development after infection by DENV. Our mouse model offers the opportunity to test potential dengue vaccines and therapeutics to treat dengue hemorrhage and to test hemorrhage induction potentials of dengue viral strains.