The sudden appearance of overt human Zika virus infections that cross the placenta to damage fetal tissues, target sexual organs, and are followed in some instances by Guillain-Barré syndrome raises questions regarding whether these outcomes are caused by genetic mutations or if prior infection by other flaviviruses affects disease outcome. Because dengue and Zika viruses co-circulate in the urban Aedes aegypti mosquito–human cycle, a logical question, as suggested by in vitro data, is whether dengue virus infections result in antibody-dependent enhancement of Zika virus infections. This review emphasizes the critical role for epidemiologic studies (retrospective and prospective) in combination with the studies to identify specific sites of Zika virus infection in humans that are needed to establish antibody-dependent enhancement as a possibility or a reality.