Hormones and cytokines indirectly control the formation of osteoclasts from hemopoietic precursors by acting upon osteoblastic stromal cells and, in some cases, also upon cells of the immune system. These intermediate cells produce factors that act in a paracrine manner to influence precursor proliferation or differentiation. Successful osteoclast formation in vitro requires contact between stromal and hemopoietic cells, leading to the concept of a membrane-associated stromal cell molecule that specifically programs osteoclast differentiation. Attention has been focused further on this by the recent discovery of a soluble member of the tumor necrosis factor (TNF) receptor family which is both a product of and a ligand for osteoblastic stromal cells. Once they are formed in the presence of osteoblasts, osteoclasts are active, and hormones or cytokines do not promote the activity of mature osteoclasts, but more likely influence their survival. Of the two best known hormonal inhibitors of bone resorption in vivo, calcitonin acts directly upon osteoclasts to inhibit their activity, whereas estrogen acts indirectly, via the regulation of several cytokines.