Bortezomib is the first-in-class proteasome antagonist approved for treatment of myeloma. It is active in newly diagnosed, relapsed, and refractory patients and is now being used as a platform for combinations with other new agents for myeloma. In addition to its anti-myeloma effect, bortezomib also targets the bone microenvironment and can inhibit osteoclast formation and stimulate osteoblast activity in patients with myeloma. Potentially, combination of bortezomib with other agents that stimulate bone formation or block bone resorption will further enhance the anti-myeloma effects of bortezomib and overcome the contribution of the tumor microenvironment to myeloma growth. In this chapter, we discuss the potential mechanisms responsible for bortezomib's effects on osteoclast and osteoblast activity in myeloma.