The study investigates the physiological role of the TNF receptor (TNFR) family member, RANK, by generating RANK-deficient mice. RANK−/− mice exhibit profound osteopetrosis due to a block in osteoclast differentiation, and they lack B cells in the spleen. Additionally, RANK−/− mice have impaired lymph node formation, retaining only Peyer's patches. These findings highlight that RANK is essential for lymph node organogenesis and osteoclast differentiation. The results also show that RANK is not required for the commitment, differentiation, and functional maturation of macrophages and dendritic cells from their myeloid precursors.The study investigates the physiological role of the TNF receptor (TNFR) family member, RANK, by generating RANK-deficient mice. RANK−/− mice exhibit profound osteopetrosis due to a block in osteoclast differentiation, and they lack B cells in the spleen. Additionally, RANK−/− mice have impaired lymph node formation, retaining only Peyer's patches. These findings highlight that RANK is essential for lymph node organogenesis and osteoclast differentiation. The results also show that RANK is not required for the commitment, differentiation, and functional maturation of macrophages and dendritic cells from their myeloid precursors.