Analysis of the interferon (IFN)-α/β system over the past two decades revealed the critical roles of the IRF and Stat families of transcription factors in the regulation of this and other cytokine systems. We proposed operation of the positive feedback mechanism of the IFN gene induction, which is mediated by IRF-3 and IRF-7. We demonstrate that this mechanism is critical not only for innate immune response against viruses, but also for adaptive immune responses through induction of the maturation of dendritic cells. We also present our recent findings on a new link between the IFN signaling and tumor suppressor p53. In fact, the IFN-mediated induction of p53 gene is critical for boosting the p53-dependent apoptotic response in tumor suppression and antiviral immunity. Bone remodeling is central to maintaining the integrity of the skeletal system, wherein the developed bone is constantly renewed by the balanced action of osteoblastic bone formation and osteoclastic bone resorption. We found that IFNs and IRF/Stat factors are uniquely involved in the regulation of bone remodeling, and summarize our data on how these cytokines and transcription factors participate in maintaining the bone homeostasis.