Summary: Dengue viruses (DENV) are the mosquito-borne viruses of greatest global public health importance. DENV circulate as four serotypes with significant immunologic cross-reactivity that does not provide protection from secondary infection with heterologous serotypes. The strong association of severe dengue illness, dengue hemorrhagic fever (DHF), with heterologous secondary infection and high cytokine levels has led to a prevailing view that DHF is immunologically mediated. In vitro studies of DENV-specific T lymphocytes, clinical studies of acute DENV infection, and immunologic studies in mouse models have provided evidence that in heterologous secondary DENV infection, there is preferential activation of memory T lymphocytes with lower avidity for the infecting virus (‘original antigenic sin’) resulting in altered T-cell functional responses. In the setting of host genetic predisposition and high level viremia, with resulting high antigenic burden, we postulate that a skewed T-cell cytokine response leads to plasma leakage in DHF. A better understanding of the immune responses associated with increased or decreased risk for DHF will be of immense value for the clinical studies of candidate multivalent DENV vaccines anticipated to take place in the next several years.