Dengue virus (DENV) is a flavivirus transmitted by Aedes mosquitoes, causing a wide range of clinical symptoms, from mild flu-like illness (dengue fever, DF) to severe forms such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). DENV has four serotypes, and infection with any of them can lead to asymptomatic or severe disease. DHF/DSS is characterized by coagulopathy, increased vascular permeability, and shock. The World Health Organization (WHO) classifies DHF into four grades, with grades III and IV being more severe and associated with shock. The pathogenesis of DENV infections is complex and involves multiple factors, including viral tropism, immune responses, host genetics, and the role of soluble factors. DENV tropism for immune cells, liver, and endothelial cells (EC) plays a critical role in the pathogenesis of DHF/DSS. During primary infection, DENV infects Langerhans cells and keratinocytes, then spreads through the lymphatic system. In secondary infections, high levels of DENV-specific IgG can enhance viral infection of mononuclear cells, leading to increased viral load and severe disease. The immune response to DENV involves the production of proinflammatory cytokines, which can contribute to vascular leakage and coagulopathy. The complement system is also involved in DENV pathogenesis, with complement activation playing a role in the development of DHF/DSS. Host genetic factors, such as HLA alleles and polymorphisms in genes like TNF-α, FcγR, and TGF-β, influence susceptibility to severe DENV infections. Antibody-dependent enhancement (ADE) is a key mechanism in secondary DENV infections, where preexisting antibodies can enhance viral infection of antigen-presenting cells (APCs), leading to increased viral load and severe disease. Cross-reactive T-cell responses can also contribute to immunopathology, with CD8+ T cells playing a role in both clearing the virus and causing tissue damage. Soluble factors, including cytokines and chemokines, are involved in the pathogenesis of DHF/DSS. High levels of TNF-α, IL-6, IL-8, and IL-10 are associated with increased vascular permeability and coagulopathy. The interplay between these factors and the host's immune response determines the severity of DENV infections. The integrated view of DENV pathogenesis highlights the complex interactions between viral tropism, immune responses, host genetics, and soluble factors, which collectively contribute to the development of DHF/DSS. Understanding these mechanisms is crucial for developing effective strategies to improve patient management and prevent severe dengue disease.Dengue virus (DENV) is a flavivirus transmitted by Aedes mosquitoes, causing a wide range of clinical symptoms, from mild flu-like illness (dengue fever, DF) to severe forms such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). DENV has four serotypes, and infection with any of them can lead to asymptomatic or severe disease. DHF/DSS is characterized by coagulopathy, increased vascular permeability, and shock. The World Health Organization (WHO) classifies DHF into four grades, with grades III and IV being more severe and associated with shock. The pathogenesis of DENV infections is complex and involves multiple factors, including viral tropism, immune responses, host genetics, and the role of soluble factors. DENV tropism for immune cells, liver, and endothelial cells (EC) plays a critical role in the pathogenesis of DHF/DSS. During primary infection, DENV infects Langerhans cells and keratinocytes, then spreads through the lymphatic system. In secondary infections, high levels of DENV-specific IgG can enhance viral infection of mononuclear cells, leading to increased viral load and severe disease. The immune response to DENV involves the production of proinflammatory cytokines, which can contribute to vascular leakage and coagulopathy. The complement system is also involved in DENV pathogenesis, with complement activation playing a role in the development of DHF/DSS. Host genetic factors, such as HLA alleles and polymorphisms in genes like TNF-α, FcγR, and TGF-β, influence susceptibility to severe DENV infections. Antibody-dependent enhancement (ADE) is a key mechanism in secondary DENV infections, where preexisting antibodies can enhance viral infection of antigen-presenting cells (APCs), leading to increased viral load and severe disease. Cross-reactive T-cell responses can also contribute to immunopathology, with CD8+ T cells playing a role in both clearing the virus and causing tissue damage. Soluble factors, including cytokines and chemokines, are involved in the pathogenesis of DHF/DSS. High levels of TNF-α, IL-6, IL-8, and IL-10 are associated with increased vascular permeability and coagulopathy. The interplay between these factors and the host's immune response determines the severity of DENV infections. The integrated view of DENV pathogenesis highlights the complex interactions between viral tropism, immune responses, host genetics, and soluble factors, which collectively contribute to the development of DHF/DSS. Understanding these mechanisms is crucial for developing effective strategies to improve patient management and prevent severe dengue disease.