Mosquitoes are essential vectors for major human diseases such as malaria and dengue fever, which together infect hundreds of millions each year, killing millions. Current approaches to disease prevention, which include anti-pathogen drugs and vector suppression through the use of insecticides or environment modification, are insufficient. Replacement of wild mosquito populations with genetically modified counterparts that cannot transmit disease provides an alternative approach to disease prevention. However, mosquitoes carrying genes for disease refractoriness are not expected to have a higher fitness than native mosquitoes, and wild populations are large, dispersed over wide areas, and partially reproductively isolated. Thus, effective population replacement requires that genes conferring disease refractoriness be coupled with a genetic mechanism for driving these genes through the wild population at greater than Mendelian frequencies. We have developed a synthetic selfish genetic element (Medea) that can spread rapidly through a population, even if its presence or that of a linked cargo results in a fitness cost. Medea is the only selfish genetic element that has multiple features required for scientific and social acceptance of transgene release into the wild: the selfish genetic element and its cargo remain tightly linked; possibilities for horizontal spread within other species are limited; transgene recall from the wild and/or cycles of population replacement can be carried out. We will develop Medea and related drive mechanisms for several important mosquito vector species. This work will be carried out in collaboration with others who have developed transgenes conferring disease refractoriness and/or who can carry out cage trials to study selfish element/effector spread and efficacy in populations of uninfected and infected mosquitoes. My goal is to bring population replacement technology to the stage where it can be applied successfully, and the communities involved will have enough confidence the technology can be controlled to allow its use.