The molecular and physiological mechanisms of control of osteoclast formation and activity have been explained with the discovery of three members of the Tumour Necrosis Factor superfamily. Receptor activator of NF-kB ligand (RANKL) is the type II membrane protein in cells of the osteoblastic lineage which interacts with its receptor, RANK, on hemopoietic precursors to promote osteoclast formation and maintain their viability and activity. The process is further regulated by the decoy receptor, osteoprotegerin (OPG), also produced by stromal/osteoblastic cells, and which binds to RANKL to prevent RANKL stimulation of osteoclast formation. These discoveries fulfilled predictions that came from more than 20 years of research in bone cell biology in predominantly rodent systems. The hypothesis that the osteoblast lineage directed osteoclast function introduced the concept of intercellular communication in bone. It needed new methods to be developed to test it, and there were many who contributed to this. With a number of identifiable milestones from the early 1980s on, a highly convincing case was made for the existence of what turned out to be RANKL and RANK. As it happened, OPG came first, and the background biological information was so instructive that it was obvious that OPG would lead to the final answer. By that stage the necessary methods were all in place, and in a short time all the key molecular regulators were identified. Ultimate proof of their physiological importance came from genetic experiments in mice.