Periodontitis, one of the most common infectious diseases in humans, is a unique “osteoimmune” disease in which antibacterial immune response causes alveolar bone destruction. Recently, it was revealed that the osteoclastic bone damage that occurs during periodontitis is dependent on the receptor activator of NF-kB ligand (RANKL) produced by osteoblastic cells and periodontal ligament cells (Tsukasaki et al., Nature Commun 2018, Nature Rev Immunol 2019). To understand the pathogenesis of and develop future therapeutic strategies for periodontal bone loss, it is vitally important to clarify precise molecular mechanisms underlying osteoclastic bone erosion. Recently, we unveiled the importance of the tight regulation of RANKL activity by the local OPG production in bone and immune systems by generating OPG-floxed mice (Tsukasaki et al., Cell Rep 2020), and deciphered the stepwise cell fate decision pathways during osteoclastogenesis at single-cell resolution (Tsukasaki et al., Nature Metabolism 2020). In this talk, I will summarize the recent progress in the fields of periodontology and RANKL biology.