Mosquitoes such as Aedes aegypti are disease vectors that rely on their keen senses to locate human hosts, and for finding conspecifics, so that they can mate. However, we have only a rudimentary understanding of the receptors that control these critical behaviors. The goal of the proposed research is to address this gap. To find human hosts, female Ae. aegypti integrate information from diverse stimuli, including CO2, visual cues, organic molecules, and skin temperature. We have discovered another cue. Aim 1 builds on our preliminary data that Ae. aegypti use infrared (IR) radiation as an additional host stimulus. We outline experiments to reveal the IR-sensing neurons, and the receptor that detects IR. To pursue this aim, we devised a highly effective behavioral assay for monitoring IR attraction, and a new molecular genetic approach to bypass complications in combining multiple genetic elements. Aim 2 takes advantage of a mutation that we recently created in a TRP channel, which renders males and females deaf. We will test the roles this channel and hearing in swarm formation, mating and in finding human hosts. Our proposed experiments will interrogate the iconoclastic idea that mosquitoes are attracted to human speech. This would be a particularly specific cue to help them recognize and zero in on people. In Aim 3, we propose a new strategy to overcome a major impediment limiting the efficacy of the sterile insect technique (SIT). SIT is a promising strategy to suppress Ae. Aegypti. It involves inundating a local population with sterile males, which render females sterile upon mating. However, an impediment to lasting suppression of mosquito populations is that wild-type males outcompete the sterile males. We propose two complementary approaches to significantly elevate male mating success. This work has the potential to transform SIT, and thereby effectively suppress Ae. aegypti. Aim 4 concerns another key sensory issue—identification of the receptors for repellents. We recently discovered that rhodopsins function as multi-modal sensory receptors, challenging 100 years of dogma that they detect only light. Here, we propose to test the hypothesis that an opsin in Ae. aegypti functions as a highly sensitive receptor for naturally-occurring insect repellents. If confirmed by our proposed experiments, this would demonstrate that opsins comprise a new, unsuspected class of olfactory receptor. To accomplish our goals, we will bring to bear an extensive repertoire of state-of-art approaches, some of which we have developed specifically to pursue this project. These include new molecular genetic tools, a suite of behavioral assays, original video tracking software, and several types of electrophysiological recordings. In summary, the unifying theme in this project is the identification of elusive receptors and mechanisms through which mosquitoes sense human hosts and conspecific mates. The insights gleaned from this work have exciting potential to l...