Osteoimmunology is an interdisciplinary field addressing the interplay between the skeletal and the immune system. A substantial body of evidence demonstrated the existence of two-way regulatory mechanisms that affect both systems, placing them in much closer association to each other than one could ever predict. Inflammatory diseases have long been known to induce alterations in bone metabolism, and inflammatory cytokines play prominent roles in the control of bone resorption, representing communication pathways bridging the two systems. Osteoclasts are particularly linked to the immune cells because they belong to the monocyte/macrophage family, have tight relationships with B and T cells, and differentiate in response to RANKL which is also produced by lymphocytes and regulates lymphopoiesis. Osteoclasts are negatively regulated by cytokines and other factors known for their anti-inflammatory and immune regulatory activity. Finally, they express immune co-receptor typical of immune cells which are indispensable for their differentiation, thus leading to the hypothesis that osteoclasts are immune cells themselves. The underlying principle why an immune cell is required to resorb bone has not yet been elucidated. Data from early literature suggest that the bone matrix could trigger an innate immune response activating giant cells that could destroy large bone areas because of their unique property of resorbing bone extracellularly. Bone resorption could though be prevented by the physical barrier made by osteoblasts and lining cells, whose retraction would be required to give access to osteoclasts when specific pathways signal their precursors to differentiate and mature osteoclasts to reach the uncovered bone surface.