The endocannabinoid system plays an important role in numerous physiological processes and represents a potential drug target for diseases ranging from brain disorders to cancer. Recent preclinical studies implicated endocannabinoids and their receptors in the regulation of bone cell activity and in the pathogenesis of bone loss. Cells and intervening nerves in the skeleton express cannabinoid receptors and the machinery for the synthesis and breakdown of endocannabinoids. In healthy adult mice, pharmacological and genetic inactivation of the cannabinoid type 1 receptor (CB1) and putative cannabinoid receptor GPR55 (G protein-coupled receptor 55) inhibit osteoclastic bone resorption and increase bone mass, suggesting that both receptors have a negative role in early bone development. Although no distinct abnormalities in bone development were observed in healthy adult mice deficient in cannabinoid type 2 receptors (CB2), pharmacological blockage of this receptor was effective in suppressing bone loss associated with increased bone turnover, particularly in mouse models of osteoporosis, arthritis and osteolytic bone disease. In the aging skeleton, CB1 deficiency causes accelerated osteoporosis characterized mainly by a significant reduction in bone formation coupled to enhanced adipocyte accumulation in the bone marrow. A similar acceleration of bone loss was also reported in aging CB2-deficient mice but found to be associated with enhanced bone turnover. This perspective describes the role of cannabinoid ligands and their receptors in bone metabolism and highlights the promise and dilemma of therapeutic exploitation of the endocannabinoid system for treatment of bone disorders.