Background: Most human research on leptin has involved well-nourished subjects or clinical states such as anorexia nervosa or cancer cachexia. Objective: We studied the development of leptin as a monitor of energy status in young African infants whose growth patterns probably reflect the evolutionary norm. Design: We enrolled a prospective birth cohort of 138 rural Gambian mother-infant pairs. Plasma leptin was analyzed in maternal blood in late pregnancy, in cord blood, and at 8, 16, and 52 wk in the infants. Body mass index (BMI; in kg/m(2)) was used as a proxy for fatness. The mothers were lean (BMI: 21.6 +/- 2.5), and the infants grew poorly compared with Western standards (average weight-for-age z score of -1.9 at 52 wk). Results: Maternal and cord blood leptin and birth weight were all positively correlated. Throughout infancy, leptin was highly correlated with BMI. A strong sex difference existed at birth (ie, leptin concentrations were significantly higher in females than in males), disappeared at 8 wk, and reappeared at 16 and 52 wk. Absolute leptin concentrations declined by almost 90% from birth to 52 wk, but leptin's ability to discriminate across a range of BMI values improved with age. In early infancy, leptin concentrations were uncorrelated with recent changes in BMI, but, by 52 wk, leptin was able to assess both the size of energy stores and the direction of recent changes. Conclusions: Leptin concentrations signal energy status from fetal life onward. As infancy progresses, leptin's power to discriminate both chronic and dynamic energy status increases, and this discrimination is achieved at much lower circulating peptide concentrations.