Myeloma bone disease is due to interactions of myeloma cells with the bone marrow microenvironment, and is associated with pathologic fractures, neurologic symptoms and hypercalcemia. Adjacent to myeloma cells, the formation and activation of osteoclasts is increased, which results in enhanced bone resorption. The recent characterization of the essential cytokine of osteoclast cell biology, receptor activator of NF-κB ligand (RANKL) and its antagonist osteoprotegerin (OPG), have led to a detailed molecular and cellular understanding of myeloma bone disease. Myeloma cells induce RANKL expression in bone marrow stromal cells, and direct RANKL expression by myeloma cells may contribute to enhanced osteoclastogenesis in the bone microenvironment in myeloma bone disease. Furthermore, myeloma cells inhibit production and induce degradation of OPG. These effects result in an increased RANKL-to-OPG ratio that favors the formation and activation of osteoclasts. Patients with myeloma bone disease have inappropriately low serum and bone marrow levels of OPG. Specific blockade of RANKL prevented the skeletal complications in various animal models of myeloma, and suppressed bone resorption in a preliminary study of patients with myeloma bone disease.