RANK is essential for osteoclast and lymph node development. This study investigated the physiological role of RANK, a member of the TNF receptor family, by generating RANK-deficient mice. RANK-deficient mice exhibited profound osteopetrosis due to a block in osteoclast differentiation. RANK was not required for the commitment, differentiation, and functional maturation of macrophages and dendritic cells but was necessary for the differentiation of myeloid-derived osteoclasts. RANK-deficient mice also showed a marked deficiency of B cells in the spleen and lacked all other peripheral lymph nodes, highlighting RANK's role in lymph node formation. These findings demonstrate that RANK provides critical signals for lymph node organogenesis and osteoclast differentiation. RANKL, a TNF ligand, acts as a cognate receptor for RANK and is involved in immune cell activation and bone resorption. OPG, a second TNF-family receptor for RANKL, inhibits bone resorption by blocking osteoclast differentiation and activation. RANK-deficient mice had severe osteopetrosis, impaired B-cell development, and extramedullary hematopoiesis. However, RANK was not essential for the development and function of differentiated macrophages and dendritic cells. RANK-deficient mice showed normal DC development and function. Thymic development was normal in RANK-deficient mice. RANK-deficient mice had intact lymphoid organs but lacked all other peripheral lymph nodes. The study highlights RANK's essential role in osteoclast differentiation and lymph node formation.RANK is essential for osteoclast and lymph node development. This study investigated the physiological role of RANK, a member of the TNF receptor family, by generating RANK-deficient mice. RANK-deficient mice exhibited profound osteopetrosis due to a block in osteoclast differentiation. RANK was not required for the commitment, differentiation, and functional maturation of macrophages and dendritic cells but was necessary for the differentiation of myeloid-derived osteoclasts. RANK-deficient mice also showed a marked deficiency of B cells in the spleen and lacked all other peripheral lymph nodes, highlighting RANK's role in lymph node formation. These findings demonstrate that RANK provides critical signals for lymph node organogenesis and osteoclast differentiation. RANKL, a TNF ligand, acts as a cognate receptor for RANK and is involved in immune cell activation and bone resorption. OPG, a second TNF-family receptor for RANKL, inhibits bone resorption by blocking osteoclast differentiation and activation. RANK-deficient mice had severe osteopetrosis, impaired B-cell development, and extramedullary hematopoiesis. However, RANK was not essential for the development and function of differentiated macrophages and dendritic cells. RANK-deficient mice showed normal DC development and function. Thymic development was normal in RANK-deficient mice. RANK-deficient mice had intact lymphoid organs but lacked all other peripheral lymph nodes. The study highlights RANK's essential role in osteoclast differentiation and lymph node formation.