Osteoporosis represents a major healthcare burden, affecting approximately 10 million people aged over 50 years in the United States and with another 30 million or more at risk. One of the major contributing factors to osteoporosis is withdrawal of estrogen during menopause in women. Human and animal experiments have implicated pro-inflammatory cy-tokines as primary mediators of the accelerated bone loss at menopause including interleukin-1, tumor necrosis factor-α, and interleukin-6. Increased production of pro-inflammatory cytokines is associated with osteoclastic bone resorption in a number of disease states including rheumatoid arthritis, periodontitis, and multiple myeloma; estrogen withdrawal is associated with increased production of pro-inflammatory cytokines, and exposure of bone cultures to supernatants from activated leukocytes is associated with increased bone resorption. A major advance has been the discovery ofRANKL, its receptor RANK, and the endogenous inhibitor osteoprotegerin. The binding of RANKL to RANK is essential for the differentiation and activation of osteoclasts and mediates the actions of essentially all known stimulators of osteoclastic bone resorption. RANKL expression is heightened in post- compared with pre-menopausal women, and this effect is attenuated by estrogen replacement therapy. RANKL is also a therapeutic target; a human antibody with high specificity and affinity to RANKL is currently under clinical evaluation for the treatment of osteoporosis in post-menopausal women and of metastatic bone disease in cancer patients with bone metastasis. Early data are promising.