SUMMARY Dengue is an acute mosquito-borne viral disease that is highly prevalent throughout the tropical world. The geographic footprint of the four dengue viruses (DENV-1 to -4) that cause this disease and their Aedes mosquito vector is expanding, extending into North America and Mediterranean Europe. Furthermore, although dengue has historically been a disease that disproportionately affects children, changing population demographics and increasing travel to and from the tropics have contributed to a growing incidence in adults. Dengue in adults, particularly older adults, brings fresh and complex challenges to case management. Although dengue is now a vaccine-preventable disease, the efficacy profiles of licensed vaccines as well as those in late-stage clinical development suggest that vaccination alone would not fully retard the global expansion of dengue. Other countermeasures, including antiviral drugs, will be needed. This paper reviews the molecular interplay underlying dengue pathogenesis, including from virological and immunological perspectives, which are foundational for developing antiviral therapies and new vaccines. It also reviews the hurdles facing antiviral development and discusses new insights on dengue immunity that can guide the deployment of imperfect vaccines to begin reversing the global burden of dengue.