Genetic strategies for reducing populations of vector mosquitoes or replacing them with those that are not able to transmit pathogens benefit greatly from molecular tools that allow gene manipulation and transgenesis. Mosquito genome sequences and associated EST (expressed sequence tags) databases enable large-scale investigations to provide new insights into evolutionary, biochemical, genetic, metabolic, and physiological pathways. Additionally, comparative genomics reveals the bases for evolutionary mechanisms with particular focus on specific interactions between vectors and pathogens. We discuss how this information may be exploited for the optimization of transgenes that interfere with the propagation and development of pathogens in their mosquito hosts.