Insects live in an olfactory world, as finding food, mating partners, avoiding predators, or communicating is mostly based on odorant emission and detection. As insects represent a major challenge in our society, both in agriculture (~US$70 billion per year) and healthcare (~US$6.9 billion per year), discovery of chemicals acting on their behaviours is crucial. Insects’ olfactory neurons sense chemicals through activation of multimeric ion channels where highly variable odorant receptors are coupled with a conserved co-receptor (ORco). While ORs are sensitive to a large diversity of volatile compounds, only few synthetic agonists are known to activate ORco. To identify the binding site and the ligand diffusion pathway into ORco, multiple molecular dynamics simulations (~20 μs in total) were carried. An ion channel made up of four ORco protomers was embedded into a lipid bilayer and surrounded by several agonists. The simulation analysis provided a rational approach to guide in vivo functional assays. We identified and described the binding pathway through which the insect ORco recognize its ligands. This finding opens the way to the rational design of insect repellents. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 682286) and from the Edmond Roudnitska foundation.