Dengue is the most rapidly emerging climate-sensitive infection, and there has been a 10-fold rise in cases over the past 20 years.Severe illness is characterized by vascular leakage, organ dysfunction, and severe bleeding which occur due to the direct effects of the viral non-structural protein NS1 and an aberrant host immune response.Dengue NS1 antigen, cytokines such as IL-1β, TNF-α, and IL-6, lipid mediators such as platelet-activating factor (PAF), leukotrienes and prostaglandins, VEGF, chymase, tryptase, and MMP-9 are thought to contribute to endothelial dysfunction.Many mechanisms contribute to liver dysfunction, including prolonged shock that causes hypoxic damage, direct liver cell death due to infection with the virus, and immune-mediated effects.Bleeding following dengue virus infection occurs due to multiple mechanisms including platelet activation by NS1, serotonin, and PAF, accompanied by a wide range of other coagulation abnormalities. Dengue is the most rapidly emerging climate-sensitive infection, and morbidity/mortality and disease incidence are rising markedly, leading to healthcare systems being overwhelmed. There are currently no specific treatments for dengue or prognostic markers to identify those who will progress to severe disease. Owing to an increase in the burden of illness and a change in epidemiology, many patients experience severe disease. Our limited understanding of the complex mechanisms of disease pathogenesis has significantly hampered the development of safe and effective treatments, vaccines, and biomarkers. We discuss the molecular mechanisms of dengue pathogenesis, the gaps in our knowledge, and recent advances, as well as the most crucial questions to be answered to enable the development of therapeutics, biomarkers, and vaccines. Dengue is the most rapidly emerging climate-sensitive infection, and morbidity/mortality and disease incidence are rising markedly, leading to healthcare systems being overwhelmed. There are currently no specific treatments for dengue or prognostic markers to identify those who will progress to severe disease. Owing to an increase in the burden of illness and a change in epidemiology, many patients experience severe disease. Our limited understanding of the complex mechanisms of disease pathogenesis has significantly hampered the development of safe and effective treatments, vaccines, and biomarkers. We discuss the molecular mechanisms of dengue pathogenesis, the gaps in our knowledge, and recent advances, as well as the most crucial questions to be answered to enable the development of therapeutics, biomarkers, and vaccines.