The integrity of the skeleton depends upon bone remodeling, the permanent and controlled resorption of bone by osteoclasts (OC) and its subsequent replacement by bone-forming osteoblasts. An imbalance between bone resorption and bone formation results in osteoporosis (if bone resorption exceeds bone formation) or osteopetrosis (if bone formation exceeds bone resorption). The regulation of the balance between osteoblastic and osteoclastic activity is critical for the understanding of normal bone cell biology and forms the cellular basis of the pathogenesis of metabolic bone diseases. A variety of local growth factors and cytokines as well as systemic peptide and steroid hormones regulate the differentiation of immature precursor cells and the activity of mature cells in both the osteoblastic and the osteoclastic lineage (1–7). The differentiation of OC precursors from a macrophage-like stem cell into the mature multinucleated OC (osteoclastogenesis) depends on various local factors secreted by bone marrowresiding pluripotent stromal cells and mature osteoblasts (1–3, 7). Regulation of osteoclastogenesis (and OC activity) by osteoblastic factors may therefore couple osteoclastic bone resorption to osteoblastic bone formation, and may constitute a local regulatory mechanism for bone remodeling. During the last decade evidence has emerged that osteoclastogenesis requires the presence of stromal cells, 1a,25-dihyroxyvitamin D3 (1a,25-(OH)2D3) and glucocorticoids in vitro (1–3, 7). Although extensive in vitro studies and animal experiments using knock-out or transgenic mice have identified various candidate cytokines that are capable of regulating osteoclastogenesis (and are variably produced by stromal cells treated with 1a,25-(OH)2D3 and/or glucocorticoids), until recently no single cytokine has been identified that is both necessary and sufficient to induce osteoclastogenesis. The recent discovery of osteoprotegerin (OPG)/ osteoclastogenesis inhibitory factor (OCIF) (8, 9), a soluble member of the tumor necrosis factor (TNF) receptor (TNFR) superfamily, and the subsequent identification of its cognate ligand, osteoprotegerin ligand (OPG-L)/osteoclast differentiation factor (ODF) (10, 11) (Table 1), has provided new insights into the regulation of osteoclastogenesis. TNF-related ligands and their receptors are critical for various aspects of cell survival and cell death (12). This review summarizes the rapidly evolving progress made in our understanding of OPG/OCIF and OPG-L/ ODF, including their protein and gene organization, their expression and regulation, and their effects both in vitro and in vivo. These novel findings have led to a new paradigm of osteoclast biology with major novel implications for bone metabolism and the pathogenesis of metabolic bone diseases.