Insect repellents are important prophylactic tools for travelers and populations living in endemic areas of malaria, dengue, encephalitis, and other vector-borne diseases. DEET (N,N-diethyl-3-methylbenzamide) is a 6-decade-old synthetic repellent, which is still considered the gold standard of mosquito repellents. Mosquitoes use their sense of smell to detect DEET, but there are currently two hypotheses regarding its mode of action: activation of ionotropic receptor IR40a vs. odorant receptor(s). Here, we demonstrate that DEET, picaridin, insect repellent 3535, and p-menthan-3,8-diol activate the odorant receptor CquiOR136 of the southern house mosquito, Culex quinquefasciatus. Electrophysiological and behavioral assays showed that CquiIR40a knockdown had no significant effect on DEET detection and repellency. By contrast, reduction of CquiOR136 transcript levels led to a significant decrease in electroantennographic responses to DEET and a complete lack of repellency. Thus, direct activation of an odorant receptor, not an ionotropic receptor, is necessary for DEET reception and repellency in Culex mosquitoes. Interestingly, methyl jasmonate, a repellent derived from the nonvolatile jasmonic acid in the signaling pathway of plant defenses, elicited robust responses in CquiOR136•CquiOrco-expressing Xenopus oocytes, thus suggesting a possible link between natural products with long insect-plant evolutionary history and synthetic repellents.