The pathophysiological basis of severe dengue disease (i.e., dengue hemorrhagic fever [DHF]), appears to be multifactorial, involving complex interactions among viral factors, host genetics, and the immunologic background of the host, principally prior exposure to dengue virus. Analysis of these processes has been limited to observational studies of naturally infected humans because there have not been useful animal models of dengue disease. Substantial evidence points to dengue virus-reactive T cells as a critical effector in the development of DHF. We are beginning to define the critical elements of T-cell epitope specificity and functional responses that contribute to DHF. Additional studies in well-characterized patient cohorts from different geographic regions will be needed to advance this research and guide new approaches to prevention and treatment of DHF.