ABSTRACT Mosquitoes use their olfactory and gustatory systems to find and land on a human host’s skin for a blood meal, and in the process transmit diseases like Dengue to hundreds of millions of people worldwide. Therefore, the two chemosensory systems are excellent targets for behavior disruption strategies. The gustatory system, in particular, plays the most critical role in avoidance of the synthetic topical insect repellent DEET, however it has not been leveraged for discovery of improved repellents. There is a huge need for better topical repellents; the poor cosmetic properties and high cost for frequent application on the skin preclude the use of DEET by high- risk populations in tropical countries. We reasoned that new behavioral actives could be identified from human skin-associated compounds, the rationale being that anthropophilic mosquitoes, such as Aedes aegypti, exhibit different preferences for individual humans based on differences in skin chemistry. In a recent breakthrough we developed a Machine Learning cheminformatic method to predict odorant and tastant repellents from in silico screening of skin-associated compounds. In preliminary testing using behavior assays, we found powerful repellent effects from components of skin volatiles, sweat and even microbiome metabolites. The overarching goal of this proposal is to identify skin compounds that affect close-range mosquito landing behavior and perform an analysis of the cellular and receptor pathways (Or, Ir, Gr or TrpA1) that are required to sense these compounds in olfactory and gustatory neurons of Ae. aegypti. The objective will be achieved via three specific aims. First, we will validate the computationally-predicted skin repellents in mosquito behavioral assays designed to evaluate close-range (olfactory) and contact-dependent (gustatory) effects, which will create priority lists for the following aims. Second, compounds that act upon contact or are non-volatile will be prioritized for surveying gustatory responses with single sensillum electrophysiology and in assays to examine residency and probing behaviors, which occur after landing in preparation for blood feeding. Testing Gr and Ir co-receptor mutants will identify chemoreceptor pathways involved in sensing any taste-active repellents. Third, compounds that are low- volatility and act at close range (like DEET) will be prioritized for surveying olfactory responses with electrophysiology. Contributions of chemoreceptor pathways involved in sensing the olfaction-active repellents will be identified by testing Orco and Ir co-receptor mutants. Finally, we will test if blends of predicted skin repellents that act on both olfactory and gustatory pathways can alter host attractiveness. Successful completion of this proposal will provide a foundation for understanding how aversive components of complex skin-associated cues can alter mosquito-host interactions at close range.