The RANKL/RANK/OPG system, discovered in the mid-1990s, has revolutionized our understanding of bone modeling and remodeling. This system regulates osteoclast formation, activation, and survival, both in normal bone turnover and in various pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK, thus maintaining the balance between bone formation and resorption. The relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. The discovery of this system has led to significant advances in the understanding of bone biology and has informed the development of specific inhibitors, such as OPG and monoclonal antibodies to RANKL, which have been tested in clinical trials for the treatment of bone diseases. However, long-term effects of these inhibitors on other tissues and immune responses remain to be fully elucidated.The RANKL/RANK/OPG system, discovered in the mid-1990s, has revolutionized our understanding of bone modeling and remodeling. This system regulates osteoclast formation, activation, and survival, both in normal bone turnover and in various pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK, thus maintaining the balance between bone formation and resorption. The relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. The discovery of this system has led to significant advances in the understanding of bone biology and has informed the development of specific inhibitors, such as OPG and monoclonal antibodies to RANKL, which have been tested in clinical trials for the treatment of bone diseases. However, long-term effects of these inhibitors on other tissues and immune responses remain to be fully elucidated.