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Dengue is a major public health concern throughout the tropical and sub-tropical regions of the world. It is the most rapidly spreading mosquito-borne viral disease, with a 30-fold increase in global incidence over the past 50 years. Infection with any of the Dengue virus serotypes can be asymptomatic, cause the classic dengue fever, or evolve to severe disease, which leads to hypovolemic shock and death if untreated. There is no approved specific treatment, prognostic markers, or vaccines for dengue, in part because there is insufficient knowledge of dengue pathogenesis. In this e-book, we will focus on what we believe to be a true challenge in dengue research: to understand host–pathogen interactions. Disease development results from the interaction between host and viral factors, in which the host immune response is critical. Recent advances in dengue experimental models together with clinical data have provided useful information indicating that severe dengue hallmarks (excessive production of pro-inflammatory cytokines, endothelial activation, and plasma leakage) are immune-mediated events. We hope to present readers with a comprehensive description of the immune response to the Dengue virus, detailing how DENV unbalances host homeostasis.