AbstractBACKGROUNDN,N‐Diethyl‐meta‐toluamide (DEET) is the prophylactic insect repellent used most widely to inhibit insect bites. Despite its use since 1944, the mechanism of DEET repellency remains controversial. Here, we revisited the role of smell and taste in DEET repellence using Drosophila as a model.RESULTSAnalysis of the responses of individual olfactory receptor neuron (ORN) classes to DEET reveals that 11 ORNs are activated and two are inhibited by this compound. Blocking individual ORN classes in the antenna does not block DEET repellence. This argues against the existence of a single ORN mediating DEET repellence in Drosophila. Activation of all ORCO‐expressing neurons using channelrhodopsin favors attraction, not repellence, in behavioral valence. We also demonstrate that gustatory neurons are highly sensitive to DEET. We used RNA interference to screen candidate receptors encoded by gene families involved in the detection of bitter compounds, including 34 gustatory receptors (Grs), 14 ionotropic receptors (Irs), five pick‐pocket subunits (PPKs), three transient receptor potential ion channels (TrpA, TrpL, Painless) and one metabotropic glutamate receptors gene (DmXR). We saw striking defects in DEET‐mediated oviposition behavior when expression of either Gr32a or Gr33a was inhibited.CONCLUSIONOur findings support a multimodal mechanism for DEET detection in fruit flies and indicate a prominent role for taste detection mediating DEET repellence. © 2019 Society of Chemical Industry