Background and purpose: Both CB(1) and CB(2) cannabinoid receptors have been shown to play a role in bone metabolism. Crucially, previous studies have focussed on the effects of cannabinoid ligands in murine bone cells. This study aimed to investigate the effects of cannabinoids on human bone cells in vitro. Experimental Approach: Quantitative RT-PCR was used to determine expression of cannabinoid receptors and liquid chromatography-electrospray ionisation tandem mass spectrometry was used to determine the presence of endocannabinoids in human bone cells. The effect of cannabinoids on human osteoclast formation, polarisation and resorption was determined by assessing the number of cells expressing a(v) ß(3) or with F-actin rings, or measurement of resorption area. Key Results: Human osteoclasts express both CB(1) and CB(2) receptors. CB(2) expression was significantly higher in human monocytes compared to differentiated osteoclasts. Furthermore, the differentiation of human osteoclasts from monocytes was associated with a reduction in 2-AG levels and an increase in AEA levels. Treatment of osteoclasts with LPS significantly increased levels of AEA. Nanomolar concentrations of AEA and the synthetic agonists CP 55,940 and JWH015 stimulated human osteoclast polarisation and resorption; these effects were attenuated in the presence of CB(1) and/or CB(2) antagonists. Conclusions and Implications: Low concentrations of cannabinoids activate human osteoclasts in vitro. There is a dynamic regulation of the expression of the CB(2) receptor and the production of the endocannabinoids during the differentiation of human bone cells. The data suggest that small molecules modulating the endocannabinoid system may be important therapeutics in human bone disease.