The dengue virus (DENV) belongs to the flavivirus family.Each of the four distinct serotypes of this virus can cause severe human disease, especially in tropical and subtropical areas.Majority of people infected with DENV have flu-like self-limited symptoms called dengue fever, which has a fatality rate of ≤5%.However, a small portion of patients emerges with severe manifestations referred to as dengue hemorrhagic fever, which has a high mortality rate if not treated promptly.The complex interactions between various factors (DENV serotype and individual immune status) and some obstacles (such as the lack of suitable animal models) codetermine the slow development in DENV-specific treatment.The human immune system, which plays important roles throughout the whole process of DENV infection, has been confirmed to have double-edged effects on DENV infection.Much attention has been paid to the genetic heterogeneity of molecules involved in the host immune response to DENV infection.This heterogeneity proved to be the determining factor for DENV disease orientation.The present review discusses the primary functions and single nucleotide polymorphisms of some critical molecules in the human DENV immunological defense, especially the polymorphism locus associated with the susceptibility and pathogenesis of severe DENV disease outcome.