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The olfactory system has become an important functional gateway to understand and analyze neuromodulation since olfactory dysfunction and deficits have emerged as prodromal and, at other times, as first symptoms of many of neurodegenerative, neuropsychiatric and communication disorders. Considering olfactory dysfunction as outcome of altered, damaged and/or inefficient olfactory processing, in the current review, we analyze how olfactory processing interacts with the endocannabinoid signaling system. In the human body, endocannabinoid synthesis is a natural and on-demand response to a wide range of physiological and environmental stimuli. Our current understanding of the response dynamics of the endocannabinoid system is based in large part on research advances in limbic system areas, such as the hippocampus and the amygdala. Functional interactions of this signaling system with olfactory processing and associated pathways are just emerging but appear to grow rapidly with multidimensional approaches. Recent work analyzing the crystal structure of endocannabinoid receptors bound to their agonists in a signaling complex has opened avenues for developing specific therapeutic drugs that could help with neuroinflammation, neurodegeneration, and alleviation/reduction of pain. We discuss the role of endocannabinoids as signaling molecules in the olfactory system and the relevance of the endocannabinoid system for synaptic plasticity., (© 2021 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)