Four dengue viruses (DENV) cause syndromes that are self-limited or severe. The severe syndrome, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), characterized by sudden vascular permeability, is not caused by inherently virulent DENV. This syndrome has consistently been observed to accompany dengue infections in individuals circulating heterotypic dengue antibodies at enhancing concentrations. In humans, dengue infections target monocytes/macrophages where, absent neutralization, heterotypic antibodies, perhaps directed at domain I-II of the envelope protein form immune complexes, attach to Fc receptors, suppress innate immunity, and increase productive infection. Diverse clinical responses to primary infections with different DENV strains do occur and occasionally result in subclinical vascular permeability observed as hypovolemia. The fact that American (AM) genotype DENV 2 produce only mild disease during secondary dengue infections is best explained by the downregulation of disease by DENV 1 antibodies directed at a unique antigenic structure expressed on AM DENV 2.