Receptor activator of nuclear factor XB ligand (RANKL) belongs to the TNF superfamily of cytokines. It plays a key role in osteoclastogenesis, activation, and survival of osteoclasts. The differentiation of macrophage/monocyte-like cells into osteoclasts critically depends on the binding of monocyte-colony stimulating factor (M-CSF) and RANKL by their respective plasma-membrane receptors, c-Fms and RANK. Osteoprotegerin (OPG), a soluble protein of the TNF receptor superfamily that is synthesized mainly by osteoblasts, is a decoy receptor that binds RANKL. In this way OPG competes with RANK what results in the inhibition of osteoclastogenesis and bone resorption. It has been shown that the RANKL/OPG ratio may determine the delicate balance between bone resorption and synthesis. Under normal conditions RANKL is mainly produced by osteoblasts and bone marrow stromal cells. However, in many pathological conditions such as rheumatoid arthritis (RA) and neoplastic osteolysis RANKL is also produced by T and B lymphocytes, macrophages/ monocytes, fibroblasts, synoviocytes, and megakaryocytes. In RA osteolysis is promoted not only by M-CSF and RANKL, but also by other cytokines (TNF, IL-1beta, IL-6, IL-7, IL-11, IL-15, IL-17, IL-18), hormones (PTH, PTH-rP, corticosteroids), and prostaglandin E2. On the contrary, OPG, interferon gamma, IL-4, TGF-beta, bifosfonians, and estrogens inhibit RA-associated osteoclastogenesis. Recently, therapeutics for pathological bone destruction targeting RANKL pathways have been used for the treatment of postmenopausal osteoporosis.