In destructive bone lesions of multiple myeloma (MM), osteoclastic bone resorption is enhanced, while bone formation is suppressed with impaired osteoblast differentiation from their progenitor cells. As a result, a strong negative balance in bone turnover develops in MM bone lesions. The suppression of bone formation is mainly due to a secretion of Wnt signal inhibitors, secreted Frizzled-related protein (sFRP)-2 and 3 and dikkopf1 (DKK1). In addition, the enhanced bone resorption in MM bone lesions causes a marked increase in the release and activation of transforming growth factor (TGF)-β. Although TGF-β enhances the recruitment and proliferation of osteoblast progenitors, TGF-β potently inhibits later phases of osteoblast differentiation and maturation and suppresses matrix mineralization. Thus, TGF-β also plays a role in the suppression of bone formation in MM bone lesions. In fact, when TGF-β action is suppressed by inhibitors of TGF-β type I receptor kinase, the inhibition of terminal differentiation of osteoblasts and mineralization is abrogated. While immature mesenchymal stromal cells support the growth and survival of MM cells, mature osteoblasts enhance MM cell apoptosis and cell cycle arrest. Thus, the inhibition of TGF-β signaling by TGF-β type I receptor kinase inhibitor causes not only an enhancement of bone formation but also a suppression of MM cell growth. Inhibition of TGF-β signaling can become a new therapeutic approach against MM.