The skeletal system has long been regarded as a metabolically inert organ; however, it is now well known that bone remodeling is continuously and dynamically carried out in order to maintain bone function and homeostasis. Recent reviews have described findings in the new field of osteoimmunology regarding the relationship between the skeletal and immune systems and their overlapping regulatory mechanisms [1] and [2]. Bone provides a microenvironment that is critical for the development of immune cells that are derived from hematopoietic stem cells (HSCs) and influence the various cytokines produced by immune cells to determine the fate of bone cells. Indeed, bone is an ideal anatomic microenvironment for HSC maintenance and differentiation, and recent data show that osteoblasts, which are bone matrix-producing cells, regulate the development of the HSC niche, from which all blood and immune cells are derived. The regulation of bone by hematopoietic and immune cells produces a variety of physiological and pathological effects. In pathological conditions such as rheumatoid arthritis (RA) and inflammatory bowel disease, infiltrating lymphocytes and other mononuclear cells provide several key factors that influence bone metabolism by altering the balance between bone-forming osteoblasts and bone-resorbing osteoclasts. Whether or not these interactions also influence normal bone homeostasis had been unclear until the discovery of RANKL (also known as TNF-related activation-induced cytokine, TRANCE) expressed in activated T cells and subsequent elucidation of its role as a pivotal factor for osteoclastogenesis, which has provided critical evidence that a physiological relationship exists between the normal immune system and bone metabolism [3], [4] and [5]. Here, we provide a brief description of the current understanding of bone cells (osteoclasts and osteoblasts) and the immune cell-derived factors that regulate these cells and affect bone metabolism.