Osteoclasts and osteoblasts are derived from hematopoietic and mesenchymal precursors, respectively. Osteoclast generation, function, and survival require RANKL signaling via its receptor, RANK, as well as mitochondrial biogenesis coupled with iron uptake through transferrin receptor 1 (TFR1) and iron supply to mitochondrial respiratory proteins; both cascades lead to increased H₂O₂ generation, which promotes osteoclastogenesis. Osteoblast generation is critically dependent on WNT/β-catenin/TCF signaling. ROS, which are primarily generated by the mitochondrial respiratory chain, activate FOXO transcription factors that suppress H₂O₂ production and decrease osteoclastogenesis. ROS also decrease the proliferation/differentiation of committed osteoblast precursors, by a diversion of β-catenin from WNT/β-catenin/TCF– to FOXO-mediated transcription. During the process of bone remodeling, bone matrix excavated by osteoclasts is replaced with new matrix produced by osteoblasts. Glucocorticoids (at supraphysiologic levels) and estrogens or androgens influence the generation and lifespan of osteoclasts and osteoblasts and the lifespan of osteocytes, at least in part, by altering redox balance. Black and red lines pointing to mature osteoclasts and osteoblasts on the bone surface and osteocytes embedded in the matrix indicate prolongation and shortening effects, respectively, on lifespan.