Periodontal disease is characterized by inflammation of the periodontal tissue and subsequent destruction of the alveolar bone. It is one of the most common infectious diseases in humans, being the leading cause of tooth loss in adults. Recently, it has been shown that the receptor activator of NF-κB ligand (RANKL) produced by osteoblasts and periodontal ligament fibroblasts critically contributes to the bone destruction caused by periodontal disease. Activation of the immune system plays an important role in the induction of RANKL during periodontal inflammation. Here we discuss the molecular mechanisms of periodontal bone destruction by focusing on the osteoimmune molecule RANKL.