Osteoclasts are highly specialized cells capable of degrading mineralized tissue and form at different regions of bone to meet different physiological needs, such as mobilization of calcium, modeling of bone structure, and remodeling of bone matrix. Osteoclast production is elevated in a number of pathological conditions, many of which lead to loss of bone mass. Whether normal or pathological, osteoclastogenesis strictly depends upon support from accessory cells which supply cytokines required for osteoclast differentiation. Only one of these cytokines, receptor activator of NFκB ligand (RANKL), is absolutely essential for osteoclast formation throughout life and is thus expressed by all cell types that support osteoclast differentiation. The central role of RANKL in bone resorption is highlighted by the fact that it is the basis for a new therapy to inhibit bone loss. This review will discuss mechanisms that control RANKL gene expression in different osteoclast-support cells and how the study of such mechanisms may lead to a better understanding of the cellular interactions that drive normal and pathological bone resorption.