Summary: Interferons (IFNs) play crucial roles in the regulation of a wide variety of innate and adaptive immune responses. Type I interferons (IFN-α/β) are central to the host defense against pathogens such as viruses, whereas type II interferon (IFN-γ) mainly contributes to the T-cell-mediated regulation of the immune responses. Studies of bone destruction associated with rheumatoid arthritis have highlighted the importance of the interaction between the immune and skeletal systems. Recently, a new research area, termed osteoimmunology, has been spawned by a series of studies focusing on the signaling networks between IFN and other cytokines in bone metabolisms. It has been revealed that IFN-γ interferes with the osteoclast differentiation induced by receptor activator of nuclear factor-κB ligand (RANKL), and this mechanism is critical for the suppression of pathological bone resorption associated with inflammation. In addition, RANKL induces the IFN-β gene in osteoclast precursor cells, and this induction constitutes a critical aspect of the negative feedback regulation mechanisms of RANKL signaling to suppress excessive osteoclastogenesis. Furthermore, a novel function of signal transducer and activator of transcription 1 (Stat1), the essential transcription factor for both type I and type II IFN responses, was revealed in the regulation of osteoblast differentiation. Collectively, these studies unveil novel aspects of the IFN system and indicate the operation of the intricate signaling network among IFN and other cytokine systems in bone remodeling, which might offer a molecular basis for the treatment of bone diseases.