Adult mesenchymal stem cells (MSCs) are a multipotent population of stem cells that can differentiate along the osteogenic, chondrogenic and adipogenic lineages. They offer a potentially exciting source of cells for engineering skeletal tissues for the treatment of osteochondral defects. Cannabinoids are lipophilic signalling molecules that interact with G-protein coupled cannabinoid (CB) receptors. Recently, the skeleton has been identified as a major endocannabinoid target through both the CB1 and CB2 cannabinoid receptors1, 2. The aim of this study was to examine the role of the CB2 receptor in the regulation of MSC viability. MSCs were isolated from the bone marrow of adult male Wistar rats and expanded in culture. MSCs were treated with the CB2 antagonist, AM630 (0.001-100µM) alone or in the presence of the CB2 agonist, JWH015 (10nM, 100nM and 1µM) for 24h and colorimetric TUNEL was performed to detect the percentage of apoptotic cells. Phospho-c Jun N-terminal kinase (JNK) and c-Jun expression were assessed by western immunoblotting. Caspase-3 activity was measured using a colorimetric assay to assess cleavage of the caspase-3 substrate, Ac-DEVD-pNA. AM630 (10 and 100µM) significantly increased the percentage of apoptosis; thus, in control conditions 9.08±0.38% (mean± S.E.M) of cells were apoptotic and this was significantly increased to 23.08±0.60% and 42.33±0.60% by AM630 at 10µM and 100µM, respectively (p<0.001, ANOVA, n=3, Newman-Keuls Multiple Comparison test) and this induction of apoptosis was prevented by JWH015 (100nM). AM630 (10µM,24h) significantly increased phospho-JNK immunoreactivty from 1.58±0.20 (mean arbitrary units ± S.E.M) to 3.00 ± 0.37 (p<0.05, n=5, Student’s t-test) and also significantly increased caspase-3 activity from 647.5±101.2 pmol pNA/min/mg to 2571±89.4 and this was significantly reduced to 1878±67.9 in cells exposed to AM630 in the presence of JWH015 (100nM; p<0.001, ANOVA, n=5, Newman-Keuls Multiple Comparison test). AM630 (10µM,24h) induced a significant increase in phospho-c-Jun activity from 0.62± 0.10 (mean arbitrary units ± S.E.M) to 1.20±0.08 and this was significantly reduced to 0.85± 0.08 in cells exposed to AM630 in the presence of JWH015 (100nM) (p<0.05, p<0.01, ANOVA, n=5, Newman-Keuls Multiple Comparison test). This study demonstrates that inhibition of the CB2 receptor leads to MSC apoptosis and suggests that activation of the CB2 receptor is necessary to maintain the survival of MSCs. This provides evidence of another cellular target for cannabinoid receptors which may be necessary for the maintenance of bone health.