Because of their diversity, abundance, and nigh ubiquity on land, insects represent the largest group of animal competitors to humanity. Insect vectors carry diseases such as malaria, yellow fever, and Zika that are responsible for hundreds of thousands of deaths each year, and agricultural loss to insect pests reaches billions of dollars annually. Because insects rely principally on olfactory cues to target hosts and food sources, their olfactory system is of great import for scientific study. The fruit fly Drosophila provides a genetically tractable and numerically simple nervous system well suited as a model for studying the detection and processing of odor cues. By developing in the fruit fly a technique for studying the detection of common insect repellants, we have discovered a novel mechanism of the detection of DEET involving widespread neuronal activation and inhibition, and find that this mechanism is conserved across mosquito species. We show that DEET induces either neuronal activation or inhibition in a manner dependent upon the identity of the odorant receptor expressed in the detecting neuron. A similar widespread effect is also found in response to noxious concentrations of basic amine compounds. Exposure to high concentrations of amines inhibits neurons across several sensillar classes and this inhibition renders them unresponsive to other odor ligands. We also find that certain amine compounds are able to reduce humidity sensing by the neurons in the coeloconic sensilla of Drosophila and that these compounds are able to reduce oviposition preference in mosquitoes. In summary, our research identifies several novel mechanisms of repellent detection and can potentially inform efforts in repellent development and pest management.