Enhanced osteoclastogenesis is an important pathological feature in several aging-associated bone diseases. Thus, research activities on osteoclastogenesis have been intense during the last ten years. There has been great progress made in this field, however, and in this review, we will focus on current advances in understanding the role of Ca2+/calmodulin signaling in osteoclastogenesis. There are two major Ca2+/calmodulin signaling pathways emerging as important in osteoclastogenesis. The first is from our recent data, which has established a specific role for calmodulin in osteoclastogenesis and, more specifically, calmodulin-dependent kinase II (CaMKII). The other is that a pathway involving RANK-Ca2+-calmodulin- calcineurin-NFAT is critical for osteoclastogenesis. Collectively, these reports highlight the importance of Ca2+/calmodulin signaling in osteoclastogenesis, which may present novel targets for the new therapeutic agents to combat bone loss. © 2005 by Begell House, Inc.