Leptin modulates energy metabolism and lung development. We hypothesize that the effects of leptin on postnatal lung development are volume-dependent from 2 to 10wks of age, and are independent of hypometabolism associated with leptin deficiency. To test the hypothesis, effects of leptin deficiency on lung maturation were characterized in age groups of C57BL/6J mice with varying Lep^ob genotypes. Quasi-static pressure-volume curves and respiratory impedance measurements were performed to profile differences in respiratory system mechanics. Morphometric analysis was conducted to estimate alveolar size and number. Oxygen consumption (VO₂) was measured to assess metabolic rate. Lung volume at 40cmH₂O airway pressure (V₄₀) increased with age in each genotypic group, and V₄₀ was significantly (P<0.05) lower in leptin-deficient (ob/ob) mice beginning at 2wks. Differences were amplified through 7wks of age relative to wild-type (+/+) mice. Morphometric analysis showed that alveolar surface area was lower in ob/ob compared to +/+ and heterozygotes (ob/+) mice beginning at 2wks. Unlike the other genotypic groups, alveolar size did not increase with age in ob/ob mice. In another experiment, ob/ob at 4wks received leptin replacement (5µg/g/day) for 8 days, and expression levels of the Col1a1, Col3a1, Col6a3, Mmp2, Tieg1 and Stat1 genes were significantly increased concomitantly with elevated V₄₀. Leptin-induced increases in V₄₀ corresponded with enlarged alveolar size and surface area. Gene expression suggested a remodeling event of lung parenchyma after exogenous leptin replacement. These data support the hypothesis that leptin is critical to postnatal lung remodeling, particularly related to increased V₄₀ and enlarged alveolar surface area.