Our recent studies in mice and humans suggest an important role for the endocannabinoid system in the regulation of skeletal remodelling and the consequent implications on bone mass and biomechanical function. Although the CB1 cannabinoid receptor has been identified in sympathetic terminals innervating the skeleton, its role in controlling bone turnover remains to be elucidated. The CB2 cannabinoid receptor is expressed in bone cells. Its bone anabolic action, including some of the mechanisms involved, has been reported in some detail, and is also inferred from the human genetic studies. These studies portray polymorphisms in CNR2, the gene encoding CB2, as important genetic risk factors for osteoporosis. Taken together, the reports on cannabinoid receptors in mice and humans pave the way for the development of (i) cannabinoid drugs to combat osteoporosis, and (ii) diagnostic measures to identify osteoporosis-susceptible polymorphisms in CNR2.