Large case control gene association studies have been performed on cohorts of dengue virus (DENV) infected patients identified in mainland Southeast Asia, South Asia and the Caribbean. Candidate genes that have shown statistically significant associations with DENV disease severity encode HLA molecules, cell receptors for IgG (FcGII), vitamin D and ICAM3 (DCSIGN or CD209), pathogen recognition molecules such as mannose binding lectin (MBL), blood related antigens including ABO and human platelet antigens (HPA1 and HPA2). In ethnic Thais with secondary infections a variety of HLA class I alleles (HLA-A 0203, 0207, A11, B 15, B 44, B 46, B 48, B 51, B 52), DCSIGN promoter polymorphisms and the AB blood group, independently associate with either susceptibility or resistance to dengue fever (DF) and the more severe dengue hemorrhagic fever (DHF). There is also evidence that some HLA associations with disease severity correlate with the DENV serotype inducing secondary infections. Taken together, there is now evidence that allelic variants of multiple gene loci involved in both acquired and innate immune responses contribute significantly to DENV disease outcome and severity. Further analysis of the genetic basis of severe DENV disease in different at risk populations may contribute to the development of new preventative and therapeutic interventions.