Objectives: The level of bone remodeling is controlled by the balance between bone formation by osteoblasts and bone resorption by osteoclasts. Many osteopenic diseases, including osteoporosis, rheumatoid arthritis, Paget's disease, and lytic bone metastases of malignancies are characterized by progressive and excessive bone resorption by osteoclasts. RANKL, a TNF family member is essential for the formation and activation of osteoclasts through RANK, TRAF6 and NF-kB. RANKL stimulates a MAP kinase, JNK, and subsequently elicits the activation of c-Jun. c-Jun forms AP-1 complexes with c-Fos that is an essential transcriptional factor for osteoclast formation. Methods: Results: We have recently shown that c-Jun is essential for RANKL-regulated osteoclast differentiation in vivo and in vitro. Moreover, we demonstrated that blockade of c-Jun signaling inhibits activation of NFAT family and NFAT2 expression in vitro as well as in a transgenic mice model in which dominant-negative c-Jun specifically overexpressed in osteoclast lineage. Our results also provided the evidence that a partnership between c-Jun/c-Fos and NFAT2 is essential for osteoclastogenesis. To clarify the role of NFAT in vivo, we generated transgenic mice in which constitutively-active NFAT1 is overexpressed under control of the TRAP gene promoter. The transgenic mice manifested severe osteoporotic phenotype due to accelerated osteoclastogenesis and bone resorption. Ex vivo experiments using the spleen cells isolated from the transgenic mice reveal that activation of NFAT1 stimulates osteoclast formation and bone resorption. Conclusions: Collectively, our results indicate that osteoclast development and its function are harmoniously and sequentially regulated by transcriptional factors including NFAT, c-Jun/c-Fos and NF-kB. We will also discuss the molecular mechanisms that controlled osteoclastic bone resorption and its apoptosis.