Publisher Summary Bone is continuously remodeled in normal individuals and this is achieved via a finely regulated balance between the processes of bone formation and resorption mediated by osteoblasts and osteoclasts, respectively. This bone remodeling is regulated, in part, by local factors including cytokines generated in the bone microenvironment. The purpose of this chapter is to summarize what is currently known about the role of cytokines and their receptors in bone remodeling. Recent advances in molecular biological techniques have meant that most of the biological activities ascribed to cytokines have now been associated with specific molecules, and their receptors identified and molecularly cloned. Several cytokines and their cognate receptors have been shown to be expressed by bone cells, marrow cells, or accessory cells in the bone microenvironment. Moreover, studies using knockout and transgenic mice have increased the understanding of the complex signal transduction mechanisms utilized by cytokines and are opening up new and exciting areas of study. Cytokines tend to be pleiotropic and multifactorial, and may have overlapping and seemingly redundant biological effects. Some of this redundancy is apparent in the receptor mechanisms and signal transduction pathways used by groups of cytokines. Classic examples that illustrate this vividly are the various cytokines belonging to the interleukin (IL)-6 family, such as IL-6, leukemia inhibitory factor, oncostatin-M, and IL-11, which utilize a common signal transduction protein known as gp130. These cytokines bind to distinct membrane-associated receptors, which form hetero- or homo-dimers upon binding to the ligand. Further, there is now a body of data derived from in vivo studies in animals which show that over- or under-production of certain cytokines cause profound effects on bone. These fundamental observations have the potential of not only increasing the understanding of the pathophysiology of osteoporosis, but also leading to new and better forms of therapy using these molecules as targets for drug discovery programs.