Osteoclasts are bone-resorbing multinuclear polykaryon that are essential for bone remodeling and are formed through cell fusion of mononuclear macrophage/monocyte-lineage hematopoietic precursors. In arthritic joints, a large number of activated osteoclasts can be detected, which are suggested to be causative of bone erosion in rheumatoid arthritis. It has been fully established that osteoclastogenesis is critically regulated by several key essential factors, such as M-CSF and RANKL. However, regarding their most characteristic property, i.e., cell fusion to form giant polykaryons, there are still miscellaneous questions to be clarified, although several molecules have been shown to be critically involved in this process. Here we review the latest knowledge about osteoclastogenic cell fusion and novel concepts underlying the characteristic phenomenon. Because cell fusion is a genuine property of mature osteoclasts, modulating this process will become a promising therapeutic tool for bone resorptive disorders in the future.