Osteoclasts are the principal, perhaps only, cells capable of destroying bone. They are highly motile cells, usually multinucleated, and of hemopoietic origin. Osteoclasts excavate characteristic pits and trails on bone by pumping protons to solubilize the mineral component (hydroxyapatite) and secreting cathepsin K, an enzyme that partly degrades the organic matrix component (mainly type I collagen) into a sealed, vacuole-like compartment adjacent to the bone surface. Osteoclast formation is regulated primarily by macrophage colony-stimulating factor (M-CSF), which promotes the differentiation of myeloid progenitors into promonocytes, and receptor activator of nuclear factor kappaB ligand (RANKL), a potent tumor necrosis factor (TNF)-like cytokine that causes the differentiation and fusion of promonocytes into osteoclasts. A soluble inhibitor, osteoprotegerin (OPG), serves as a critical modulator of RANKL action. Osteoclast formation is boosted strongly by hypoxia. The final differentiation of osteoclasts appears to require contact with matrix ligands and/or mineral, whereas activation of their resorptive machinery is dependent on local acidification. Most bone loss disorders are primarily the result of excessive osteoclast formation or activity. This is essentially because osteoclasts destroy bone much faster than it can be replaced by osteoblasts. For this reason, osteoclasts are normally quite sparsely distributed in adult bone, except at focal remodeling sites. Osteoclasts have proved to be a fruitful target for diverse and highly successful classes of drugs, including estrogen, bisphosphonates, calcitonin, anti-RANKL antibodies, and cathepsin K inhibitors.