Bone homeostasis is a function of the constant balancing acts between osteoclasts and osteoblasts, regulated by numerous factors in cellular and molecular levels. Calcineurin-NFAT pathway plays critical roles in bone homeostasis by regulating many aspects of bone development and remodeling. NFATc1 is the master transcription factor of osteoclasts, acting downstream of RANKL (receptor activator of nuclear factor-κB ligand) to control osteoclastogenesis. NFATc1 also plays important role in osteoblastogenesis, its increased nuclear occupancy in osteoblasts causes osteopetrosis by regulating chemokine and Wnt pathways. Targeting NFAT pathway may provide therapeutic avenues for treating bony disorders.