Diseases caused by arthropod-borne viruses are increasingly significant public health problems, and novel methods are needed to control pathogen transmission. The hypothesis underlying the research described here is that genetic manipulation of Aedes aegypti mosquitoes can profoundly and permanently reduce their competence to transmit dengue viruses to human hosts. Recent key findings now allow us to test the genetic control hypothesis. We have identified viral genome-derived RNA segments that can be expressed in mosquito midguts and salivary glands to ablate homologous virus replication and transmission. We have demonstrated that both transient and heritable expression of virus-derived effector RNAs in cultured mosquito cells can silence virus replication, and have characterized the mechanism of RNA-mediated resistance. We are now developing virus-resistant mosquito lines by transformation with transposable elements that express effector RNAs from mosquito-active promoters.