Odors and aromas perceived in food and in the environment result from the processing of complex chemical mixtures of volatile compounds that should be efficiently processed by the olfactory system. It is known for decades that this processing generates perceptual interactions, such as masking, synergy, or perceptual blending, which contribute to elaborating a synthetic brain representation of the chemical information. Nevertheless, the perceptual processes underlying these interactions are still poorly known. In this project, we set out a multidisciplinary approach to identify the characteristics of odorants and olfactory receptors (ORs) that could support perceptual interactions. We hypothesized that odorants involved in interactions at the peripheral level should share common structural characteristics to allow the activation of a common set of ORs. First, using an RNA-seq approach in mice, we identified the ORs responding to either single odorants or mixtures exhibiting specific perceptual interactions. Then, we confirmed that the target ORs responded to odorants in an in vitro cellular system and that the expected perceptual interactions occurred between the odorants at the olfactory periphery, through EOG recordings on mice’s olfactory mucosa, but also through sensory evaluation in humans. Additionally, a computational study revealed common molecular features between the odorants involved in interactions. When combined, all the results highlight that perceptual interactions such as masking could rise from competition between odorants at the OR level, but that other interactions such as perceptual blending most likely originate from more central integrative brain processing.Read less <