Breast and prostate cancer frequently metastasizes to the skeleton and causes bone destruction. In skeletal tissue, transforming growth factor-beta (TGF-beta) is a major bone-derived factor responsible for driving a feed-forward vicious cycle of breast cancer growth in bone. TGF-beta is released from bone in active form by osteoclastic resorption and increases the tumor secretion of factors, which stimulate osteolytic destruction of the bone adjacent to the tumor. Moreover it activates epithelial-mesenchymal transition and tumor cell invasion, increases angiogenesis and induces immunosuppression. Blocking the TGF-beta signaling pathway to interrupt this vicious cycle between tumor and bone offers a target for therapeutic intervention to decrease skeletal metastasis. Here we summarize the current knowledge of TGF-beta in bone metastases, the use of TGF-beta inhibitors and its potential for clinical use and consequences.