Leptin is thought to regulate energy balance through effects on food intake and thermogenesis. In addition, leptin may serve as a mediator of the neuroendocrine response to starvation, and may modulate the stress response and the timing of puberty. A role for leptin in development is suggested by the presence of neuroendocrine and structural neuronal abnormalities in ob/ob mice with genetic leptin deficiency. Here, we sought to determine the ontogeny of leptin expression and its relationship to the developing neuroendocrine axis. Leptin increased 5-10-fold in female mice during the second postnatal week independent of fat mass, and declined after weaning. The rise in leptin preceded the establishment of adult levels of corticosterone, thyroxine, and estradiol. In contrast to adult mice, leptin was not acutely regulated by food deprivation during the early postnatal period. Circadian rhythms of leptin, corticosterone, and thyroxine were regulated by food intake in adult mice. When ad libitum feeding was restricted to the light cycle, peak corticosterone levels were shifted to the beginning of the light cycle and coincided with the nadir of leptin. The inverse relationship between leptin and corticosterone was maintained such that a rise in leptin after feeding was associated with a decline in corticosterone. To determine whether changes in corticosterone during food restriction are mediated by leptin, we compared the patterns of corticosterone levels among ob/ob, db/db, and lean mice. Despite their higher basal levels of corticosterone, leptin deficiency in ob/ ob mice did not prevent the nocturnal rise in corticosterone. In contrast, the nocturnal surge of corticosterone was blunted in db/db mice. Therefore, it is likely that factors in addition to leptin are involved in the regulation of the circadian rhythm of corticosterone. The temporal relationship between leptin and other hormones in neonatal and adult mice suggests that leptin is involved in the maturation and function of the neuroendocrine axis.