Dengue virus (DENV) is a human pathogen that causes severe and potentially fatal disease in millions of individuals each year. Immune-mediated pathology is thought to underlie many of the complications of DENV infection in humans, but the notable limitations of the available animal models have impeded our knowledge of the interactions between DENV and the immune system. In this Opinion article, we discuss some of the controversies in the field of dengue research relating to the interaction between DENV and the mammalian host. We highlight key barriers hindering our understanding of the molecular pathogenesis of DENV and offer suggestions for the most effective ways in which the role of the immune system in the protection from, and pathology of, DENV infection can be addressed experimentally.