A new understanding of the regulation of bone resorption developed with the discovery of receptor activator of nuclear factor-kappaB, receptor activator of nuclear factor-kappaB ligand, and osteoprotegerin in 1997-1998. The RANK signaling system is abnormally regulated in multiple myeloma, and this favors increased osteoclast function, which early in the disease is compensated by increased osteoblast function. Later in the disease osteoblast activity decreases, resulting in osteolytic lesions. We review the factors implicated in osteoclast and osteoblast function. Among these are receptor activator of nuclear factor-kappaB, receptor activator of nuclear factor-kappaB ligand, osteoprotegerin, hepatocyte growth factor, macrophage inflammatory protein-1alpha, bone morphogenetic proteins, and the Wnt system. Bisphosphonates are the only drugs used in routine clinical management; however, the complex regulation system of bone homeostasis offers a number of of possible targets for therapy, which are discussed.