The article reviews the biology of the RANKL/RANK/osteoprotegerin (OPG) system, which plays a crucial role in bone resorption and remodeling. The discovery of this system in the mid to late 1990s was a significant breakthrough, as it explained how osteoclast formation and activity are regulated by factors expressed by osteoblast/stromal cells. RANKL, a member of the tumor necrosis factor superfamily, is produced by osteoblasts and stromal cells and binds to its receptor, RANK, on osteoclast precursors, promoting their differentiation and activation. OPG, produced by various tissues, binds to RANKL, preventing it from binding to RANK and thus inhibiting osteoclast formation. The ratio of RANKL to OPG is a key determinant of bone mass and skeletal integrity. Genetic studies have shown that RANKL/RANK signaling is also involved in lymph node formation, mammary gland development, and protection against medial calcification in arteries. The article discusses the molecular mechanisms underlying osteoclast formation and activation, including the role of transcription factors such as NF-κB and c-Fos, and the importance of adapter proteins like TRAF6 and Gab2. It also highlights the broader functions of RANKL/RANK signaling in other tissues, such as the cardiovascular system, and the potential therapeutic targets for bone diseases. Despite significant progress, many questions remain about the system's role in health and disease, particularly in inflammatory conditions and cancer.The article reviews the biology of the RANKL/RANK/osteoprotegerin (OPG) system, which plays a crucial role in bone resorption and remodeling. The discovery of this system in the mid to late 1990s was a significant breakthrough, as it explained how osteoclast formation and activity are regulated by factors expressed by osteoblast/stromal cells. RANKL, a member of the tumor necrosis factor superfamily, is produced by osteoblasts and stromal cells and binds to its receptor, RANK, on osteoclast precursors, promoting their differentiation and activation. OPG, produced by various tissues, binds to RANKL, preventing it from binding to RANK and thus inhibiting osteoclast formation. The ratio of RANKL to OPG is a key determinant of bone mass and skeletal integrity. Genetic studies have shown that RANKL/RANK signaling is also involved in lymph node formation, mammary gland development, and protection against medial calcification in arteries. The article discusses the molecular mechanisms underlying osteoclast formation and activation, including the role of transcription factors such as NF-κB and c-Fos, and the importance of adapter proteins like TRAF6 and Gab2. It also highlights the broader functions of RANKL/RANK signaling in other tissues, such as the cardiovascular system, and the potential therapeutic targets for bone diseases. Despite significant progress, many questions remain about the system's role in health and disease, particularly in inflammatory conditions and cancer.