Publisher Summary One of the integral cell types contributes significantly to regulation of bone mass; osteoblasts, of mesenchymal origin, are transducers of numerous endocrine and paracrine signals. Separately they secrete and calcify the unique bone matrix, which is degraded by myeloid derived osteoclasts. The mechanism by which osteoclasts resorb bone is described in this chapter. The osteoclast, the only cell capable of bone degradation, is of hematopoietic origin. Many experiments have affirmed the original finding, including many examples of bone marrow rescue replicative of the early work, plus studies in which mice lacking the early myeloid-specific gene PU.1 fail to develop osteoclasts. While it is clear that hematopoietic stem cells (HSCs) are osteoclast precursors, the initial steps in lineage development have not been defined completely. Thus, the earliest precursor that can be isolated and manipulated readily in vitro is the bone marrow macrophage (BMM) or its splenic counterpart, cells which arise from HSCs by incompletely understood signaling pathways. It is possible now to generate sufficient mature murine osteoclast-like cells to perform a wide range of cell biology studies by exposing BMMs to just two cytokines, M-CSF and RANKL, whose receptors are c-Fms and RANK, respectively.