Estrogen deficiency causes a dramatic and precipitous loss of bone that can be prevented by estrogen replacement This review highlights recent evidence indicating that estrogens exert their potent influence on the skeleton by regulating the production of cytokines that promote osteoclast development in the bone marrow, such as interleukin-6 (IL-6). Indeed, it has been found that in the estrogen-replete state, the production of IL-6 by bone marrow stromal cells and osteoblastic cells is inhibited by estrogens through an estrogen receptor-mediated inhibitory effect on the transcriptional activity of the IL-6 gene promoter. In the estrogen-deficient state, the inhibitory effect of estrogens on IL-6 is removed, resulting in enhanced osteoclastogenesis. This evidence provides for the first time a mechanistic explanation for the protective effect of estrogens on bone homeostasis and points to IL-6 as a critical pathogenetic factor in the bone loss caused by estrogen deficiency. Whether other cytokines also play a role in this pathologic process remains unclear.