Over three billion are at risk of dengue infection with more than 100 million a year presenting with symptoms that can lead to deadly haemorrhagic disease. There are however no treatments available and the only licensed vaccine shows limited efficacy and is able to enhance the disease in some cases. These failures have mainly been due to the complex pathology and lack of understanding of the correlates of protection for dengue virus (DENV) infection. With increasing data suggesting both a protective and detrimental effect for antibodies and CD8 T-cells whilst having complex environmental dynamics. This review discusses the roles of genomic and immunological aspects of DENV infection, providing both a historical interpretation and fresh discussion on how this information can be used for the next generation of dengue interventions.