Dengue virus infections are a serious cause of morbidity and mortality in most tropical and subtropical areas of the world; Southeast and South Asia, Central and South America, and the Caribbean. Dengue virus infection can be asymptomatic or causes two forms of illness, dengue fever (DF) and dengue hemorrhagic fever (DHF), which is the severe form of dengue illness and often fatal. Pathogenesis of DHF has been analyzed, and two mechanisms are considered to be responsible. These include dengue serotype cross-reactive immune responses and virulence of the virus. The immunopathological mechanisms include a complex series of immune responses. Rapid increase in the levels of cytokines, especially TNF-alpha, and chemical mediators play a key role in inducing unique clinical manifestations of DHF such as plasma leakage, shock, and hemorrhagic manifestations. It is understood that the process is initiated by infection with a virulent dengue virus, often in the presence of antibodies that enhance dengue virus infection in secondary infection, and then triggered by rapidly elevated cytokines and chemical mediators that were produced by intense immune activation. However, complete understanding of the entire pathological mechanism is far from complete, and further studies are still needed.