Dengue virus (DENV) is transmitted to humans by *Aedes* mosquitoes, primarily *Aedes aegypti*. There are four serotypes of DENV, and infection can range from asymptomatic to severe disease, including dengue fever (DF) and dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). DF is characterized by fever, headache, and other flu-like symptoms, while DHF and DSS involve more severe complications such as hemorrhage and shock. The risk of severe disease is higher in children in Asia compared to adults in the Americas. The pathogenesis of DENV infections involves multiple factors, including viral tropism, host immune response, genetic factors, and soluble factors. Viral tropism is influenced by the infection of immune cells, liver cells, and endothelial cells (ECs). Immune cells, such as monocytes and macrophages, are infected during primary viremia, leading to virus dissemination. The liver, ECs, and bone marrow are also frequently infected, but the presence of virus in these organs does not always correlate with severe pathology. Viral virulence, as indicated by different genotypes, can influence disease severity. For example, the introduction of a more virulent DENV-2 genotype in the Americas in 1981 coincided with an increase in DHF cases. The complement system plays a crucial role in the pathogenesis of DENV infections, with high levels of activation products like C3a and C5a observed during plasma leakage. Complement activation can be triggered by the major nonstructural protein 1 (NS1) of DENV, leading to the production of inflammatory cytokines and other mediators. Cross-reactive antibodies produced during infection can also contribute to disease severity. Anti-NS1 antibodies can cross-react with ECs and platelets, leading to increased permeability and hemorrhage. Host genetic factors, such as HLA alleles and polymorphisms in genes like TNF-α and MBL2, also influence disease susceptibility and severity. Antibody-dependent enhancement (ADE) of infection can occur during secondary infections, leading to increased viral load and severe disease. Cross-reactive T cells can also cause immunopathology, with high-avidity cross-reactive CD8+ T cells producing high levels of proinflammatory cytokines and contributing to vascular permeability. Soluble factors, including cytokines and other mediators, play a critical role in the pathogenesis of DHF and DSS. High levels of cytokines like IL-1β, IL-6, and TNF-α are associated with severe disease, and these factors can induce coagulopathy and plasma leakage. In conclusion, the pathogenesis of DENV infections is complex and multifactorial, involving interactions between the virus, host immune response, and genetic factors. Understanding these interactions is essential for developing strategies to improve patientDengue virus (DENV) is transmitted to humans by *Aedes* mosquitoes, primarily *Aedes aegypti*. There are four serotypes of DENV, and infection can range from asymptomatic to severe disease, including dengue fever (DF) and dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). DF is characterized by fever, headache, and other flu-like symptoms, while DHF and DSS involve more severe complications such as hemorrhage and shock. The risk of severe disease is higher in children in Asia compared to adults in the Americas. The pathogenesis of DENV infections involves multiple factors, including viral tropism, host immune response, genetic factors, and soluble factors. Viral tropism is influenced by the infection of immune cells, liver cells, and endothelial cells (ECs). Immune cells, such as monocytes and macrophages, are infected during primary viremia, leading to virus dissemination. The liver, ECs, and bone marrow are also frequently infected, but the presence of virus in these organs does not always correlate with severe pathology. Viral virulence, as indicated by different genotypes, can influence disease severity. For example, the introduction of a more virulent DENV-2 genotype in the Americas in 1981 coincided with an increase in DHF cases. The complement system plays a crucial role in the pathogenesis of DENV infections, with high levels of activation products like C3a and C5a observed during plasma leakage. Complement activation can be triggered by the major nonstructural protein 1 (NS1) of DENV, leading to the production of inflammatory cytokines and other mediators. Cross-reactive antibodies produced during infection can also contribute to disease severity. Anti-NS1 antibodies can cross-react with ECs and platelets, leading to increased permeability and hemorrhage. Host genetic factors, such as HLA alleles and polymorphisms in genes like TNF-α and MBL2, also influence disease susceptibility and severity. Antibody-dependent enhancement (ADE) of infection can occur during secondary infections, leading to increased viral load and severe disease. Cross-reactive T cells can also cause immunopathology, with high-avidity cross-reactive CD8+ T cells producing high levels of proinflammatory cytokines and contributing to vascular permeability. Soluble factors, including cytokines and other mediators, play a critical role in the pathogenesis of DHF and DSS. High levels of cytokines like IL-1β, IL-6, and TNF-α are associated with severe disease, and these factors can induce coagulopathy and plasma leakage. In conclusion, the pathogenesis of DENV infections is complex and multifactorial, involving interactions between the virus, host immune response, and genetic factors. Understanding these interactions is essential for developing strategies to improve patient