The cannabinoid CB1 and CB2 receptors are Class A G protein-coupled receptors (GPCRs). While many Class A GPCRs have endogenous ligands that are hydrophilic cations (e.g., the serotonin and dopamine receptors), the cannabinoid receptors have neutral, highly lipophilic ligands derived from the fatty acid, arachidonic acid. The most well-studied of these are N-arachidonoylethanolamine (anandamide, AEA) and sn-2-arachidonoylglycerol (2-AG). This review focuses on the experimental and computational studies that have been used to probe the nature of endocannabinoid interaction with the cannabinoid receptors. These studies include mutation, SAR and NMR studies, as well as, QSAR, docking and molecular dynamics simulations. Gaps in our knowledge are identified. The review begins more generally, however, by discussing the entire endocannabinoid system, of which the cannabinoid receptors are part. For in order to understand endocannabinoid action, one needs an appreciation for the environments for which these ligands have been designed and the conformational changes these ligands must undergo in order to act on the cannabinoid receptors.