The secreted cytokine RANKL (Receptor Activator of Nuclear factor kappa-B Ligand) is critically involved in osteoclastic differentiation and activation and in the regulation of specific immunity. RANKL exists as a homotrimer, is glycosylated, and occurs in 3 forms: cell-bound RANKL, which is expressed by osteoblast lineage cells, soluble RANKL (sRANKL), which is expressed by activated T lymphocytes, and a truncated ectodomain form derived from the cell-bound RANK Ligand, which is enzymatically processed by TACE (TNF-alpha converting enzyme (TACE; ADAM-17)). All three forms stimulate their specific receptor, RANK, which is located on osteoclastic and dendritic cells. RANKL binds to TNFRSF11B/OPG and to TNFRSF11A/RANK. RANKL augments the ability of dendritic cells to stimulate naive T-cell proliferation. It may be an important regulator of interactions between T-cells and dendritic cells and may play a role in the regulation of the T-cell-dependent immune response. It may also play an important role in enhanced bone-resorption in humoral hypercalcemia of malignancy. Expression of RANKL is highest in the peripheral lymph nodes, weak in spleen, peripheral blood leukocytes, bone marrow, heart, placenta, skeletal muscle, stomach and thyroid and is up-regulated by T-cell receptor stimulation. RANKL is secreted in the soluble form. Defects in TNFSF11 cause osteopetrosis. Recombinant human soluble RANKL produced in E.coli is a single, non-glycosylated polypeptide chain containing 176 amino acids and having a molecular mass of 20,006 Daltons.