The two cannabinoid receptors, CB1 and CB2, are involved in many pathological processes and present attractive therapeutic targets. Recently, the ligand-bound structures of the cannabinoid receptors have been determined in high resolution using X-ray and cryo-EM approaches. The available ligand-receptor complexes, to date, have been elucidated in the presence of several agonists, antagonists, and inverse agonists, that belong to various structurally distinct classes. These structures uncovered features of the activation/deactivation mechanisms, ligand recognition elements, and their implications for drug discovery. This talk will focus on the orthosteric binding pockets of CB1 and CB2, what has been learned so far and what is more to learn regarding subtype selectivity and the functional profiles of several cannabinoid ligands. Also, comparing the CB1 and CB2 structures indicates that it is possible to obtain dual-acting ligands with opposing functions between the two receptors. The knowledge obtained sets the basis for the efficient drug discovery of cannabinoid ligands.