RANK ligand (RANKL) is a TNF-related protein that binds to, and activates, the TNFR-related protein known as RANK. Several groups studying both immune homeostasis and bone metabolism independently identified this ligand/receptor pair. The expression of RANKL suggests a role in the interaction of T cells and antigen-presenting cells during generation of immune responses, and in regulating bone resorption processes within the primary spongi-osa and cartilaginous growth plate. RANKL/RANK interactions stimulate signal transduction leading to activation of the NFkB and Jun kinase pathways, and initiate gene expression patterns that typify the osteoclast lineage.Overexpression of RANKL in mice is associated with increased bone resorption and loss of bone density, while loss of RANKL results in an absence of the osteoclast lineage and an absolute defect in bone resorption. The expression of RANKL is regulated by calciotropic hormones and proresorptive cytokines that stimulate bone resorption during physiologic and pathophysiologic conditions. Thus, RANKL ligand is essential for regulating bone density via the osteoclast and is implicated in osteopenic disorders where increased osteoclast activity is observed, such as osteoporosis and rheumatoid arthritis.