Control of osteoclastogenesis and osteoclast activity is critical for the treatment of metabolic bone diseases. The long sought after molecules that directly control the function and fate of these specialized bone-resorbing cells have recently been identified. Here we review the discovery of these molecules (receptor activator of nuclear factor κB/osteoclast differentiation and activation receptor; osteoclast differentiation factor/osteoprotegerin ligand/tumor necrosis factor-related activation-induced cytokine; and osteoprotegerin/osteoclast inhibitory factor) and the in vivo preclinical and clinical data supporting their role as dominant regulators of osteoclasts. These molecules are all members of the tumor necrosis factor receptor superfamily, which has been shown to regulate programmed cell death by either suppressing apoptosis via inducing the expression of survival genes, or initiating apoptosis through activation of the caspase cascade. In an attempt to explain the teleology of this signaling pathway and how it controls the osteoclast lifespan, we propose a model in which a loose analogy is drawn between this pathway and that of tumor necrosis factor signaling in T lymphocytes. Future experimentation to test this model will provide a better understanding of this pathway and information as to the best way to manipulate this system to treat patients with musculoskeletal disease. (C) 2000 Lippincott Williams and Wilkins, Inc.