Dengue viruses (DENV) are mosquito-borne viruses that cause significant morbidity. The existence of four serotypes of DENV with partial immunologic cross-reactivity creates the opportunity for individuals to experience multiple acute DENV infections over the course of their lifetimes. Research over the past several years has revealed complex interactions between DENV and the human innate and adaptive immune systems that can have either beneficial or detrimental influences on the outcome of infection. Further studies that seek to distinguish protective from pathological immune responses in the context of natural DENV infection as well as clinical trials of candidate DENV vaccines have an important place in efforts to control the global impact of this re-emerging viral disease.