A multitude of physiological effects and putative pathophysiological roles have been proposed for the endogenous cannabinoid system in the gastrointestinal tract, liver and pancreas. These range from effects on epithelial growth and regeneration, immune function, motor function, appetite control, fibrogenesis and secretion. Cannabinoids have the potential for therapeutic application in gut and liver diseases. Two exciting therapeutic applications in the area of reversing hepatic fibrosis as well as anti-neoplastic effects may have a significant impact in these significant diseases. This review critically appraises the experimental and clinical evidence supporting clinical application of cannabinoid receptor-based drugs on gastrointestinal, liver and pancreatic diseases. Application of modern pharmacological principles will most likely expand the selective modulation of cannabinoid system peripherally in humans. We anticipate that in addition to the approval in several countries of the CB1 antagonist, rimonabant, for the treatment of obesity and associated metabolic dysfunctions, other cannabinoid modulators are likely to have an impact on human disease in the future, including hepatic fibrosis and neoplasia.