Leptin-deficient (ob/ob) and leptin receptor (Lepr)-deficient db/db mice develop a mild form of osteoclast-rich osteopetrosis, most evident in long bone epiphyses, implying leptin is important for normal replacement of cartilage during skeletal maturation. However, it is unclear whether leptin acts as a permissive or regulatory factor and whether its actions are mediated via peripheral pathways. Here we show the osteopetrotic phenotype is not evident in ob/+ or db/+ mice, suggesting that leptin acts as a critical but permissive factor for skeletal maturation. The importance of leptin is further supported by our results showing that interventions known to increase bone resorption (mild cold stress, simulated microgravity, or particle-induced inflammation) did not advance skeletal maturation in ob/ob mice whereas long-duration hypothalamic leptin gene therapy was effective. Additionally, administration of leptin by subcutaneously implanted osmotic pumps (400 ng/h) for 2 weeks accelerated skeletal maturation in ob/ob mice. Because leptin has the potential to act on the skeleton through peripheral pathways, we interrogated osteoclast-lineage cells for the presence of Lepr and evaluated skeletal response to the introduction of bone marrow Lepr⁺ cells into db/db mice. We identified Lepr on marrow MCSFR⁺CD11b⁺ osteoclast precursors and on osteoclasts generated in vitro. We then adoptively transferred Lepr⁺ marrow cells from GFP mice or wildtype (WT) mice into Lepr^- db/db mice. Following engraftment, most MCSFR⁺ CD11b⁺ cells in marrow expressed GFP. Whereas db/db→db/db had minimal influence on epiphyseal cartilage, WT→db/db decreased cartilage. These findings suggest peripheral leptin signaling is required for normal osteoclast-dependent replacement of cartilage by bone during skeletal maturation.