The cannabinoid type 2 receptor (CB2) has previously been implicated as a regulator of tumour growth, bone remodelling and bone pain. However, very little is known about the role of the skeletal CB2 receptor in the regulation of osteoblasts and osteoclasts changes associated with breast cancer. Here, we found that the CB2 selective agonists HU308 and JWH133 reduced the viability of a variety of parental and bone-tropic human and mouse breast cancer cells at high micro-molar concentrations. Under conditions in which these ligands are used at the nano-molar range, HU308 and JWH133 enhanced human and mouse breast cancer cell-induced osteoclastogenesis and exacerbated osteolysis, and these effects were attenuated in cultures obtained from CB2 deficient mice or in the presence of a CB2 receptor blocker. HU308 and JWH133 had no effects on osteoblast growth or differentiation in the presence of conditioned medium from breast cancer cells, but under these circumstances both agents enhanced PTH induced osteoblast differentiation and ability to support osteoclast formation. Mechanistic studies in osteoclast precursors and osteoblasts showed that JWH133 and HU308 induced PI3K/AKT activity in a CB2 dependent manner, and these effects were enhanced in the presence of osteolytic and osteoblastic factors such as RANKL and PTH. When combined with published work, these findings suggest that breast cancer and bone cells exhibit differential responses to treatment with CB2 ligands, depending upon cell type and concentration used. We therefore conclude that both, CB2 selective activation and antagonism have potential efficacy in cancer associated bone disease but further studies are warranted and ongoing.