Aedes aegypti is the primary global vector for dengue virus.  There are no licensed vaccines or drugs available to prevent dengue and mosquito control remains the only option for preventing dengue.  It is well known that A. aegypti populations vary in their ability to transmit dengue virus.  It is also well documented that the innate immune system is broadly conserved across insects and mammals.  We are using a systems genetics approach to examine A. aegypti populations and their interaction with the environment and dengue virus.  This approach allows us to merge genetic data with new technology genomics data to identify and characterize metabolic pathways that determine whether an individual mosquito will be competent to transmit dengue.  We observed wide dengue susceptibility across A. aegypti populations and showed that environmental factors influence phenotype.  Based on whole genome sequence information and the total predicted gene set for A. aegypti, we compared gene expression in susceptible and refractory strains following a dengue-infected blood meal.  Our initial results with a dengue-2 isolate demonstrated that co-expression gene networks are evident in susceptible and refractory individuals.  Many of the same genes were differential expressed following exposure to dengue-1, 3 and4 isolates suggesting a common innate immune response indicative of eventual vector competence to transmit virus to humans.  These and continued studies have the potential to identify novel targets for physical or chemical intervention to prevent dengue transmission by mosquitoes, as well as development of diagnostic tools for monitoring vector competence of mosquito populations.