It is now widely recognized that the RANKL-RANK-OPG signaling system plays an important role in the differentiation, activation and cell death of osteoclasts. Recently, several genetic disorders involving the RANKL-RANK-OPG system have been discovered. In this article, we would like to show a brief review on a genetic disorder familial expansile osteolysis (FEO) , in which RANK gene mutation was identified, and other genetic disorders of the RANKL-RANK-OPG system.