The present review provides an update on endocannabinoid basic science and clinical studies and proposes a new model to describe reciprocal interactions between somatic dysfunction and the endocannabinoid system. The endocannabinoid system consists of cannabinoid receptors, endogenous ligands, and ligand-metabolizing enzymes. The system exemplifies the osteopathic principle that the body possesses self-regulatory mechanisms that are self-healing in nature. Enhancing endocannabinoid activity has broad therapeutic potential, including the treatment of patients with somatic dysfunction, chronic pain, and neurodegenerative diseases as well as inflammatory conditions, bowel dysfunctions, and psychological disorders. Blockade of the endocannabinoid system with drugs such as rimonabant and taranabant may oppose self-healing mechanisms and elicit adverse effects. Osteopathic physicians wield several tools that can augment endocannabinoid activity, including lifestyle modifications, pharmaceutical approaches, and osteopathic manipulative treatment.