The discovery and characterization of the RANKL/RANK/OPG signaling pathway and the identification of its role in the pathogenesis of bone loss have provided the rationale for the development of drugs with the ability to modulate RANK-induced osteoclastogenesis. In vivo studies have identified interfering with the RANKL/RANK interaction as a potential therapeutic target in the management of osteoporosis. Two agents capable of blocking the binding of RANKL to RANK have been so far tested in clinical studies--osteoprotegerin (Fc-OPG fusion molecule) and the RANKL-antibody (AMG 162). Both have been found to have profound inhibitory effects on bone resorption, with AMG 162 appearing to be overall superior to OPG. Data are still very scarce, however, and much remains to be uncovered before novel strategies capable of modulating the RANKL/OPG signaling pathway could be safely and effectively used in the management of osteoporosis.