Several studies have demonstrated that maternal undernutrition or overnutrition during pregnancy can have negative consequences for the health of children born to these pregnancies, but the physiological mechanisms by which this occurs are not completely understood. During periods of food restriction, concentrations of leptin decline, whereas leptin is elevated in obesity, suggesting that it may play a role in the response to altered nutrition during pregnancy. This study compares placental development and global placental gene expression profiles at Day 11.5 in pregnant control mice, mice that were undernourished, and mice that were undernourished but given leptin. Placentas from mothers exposed to food restriction preserved the placental labyrinth zone at the expense of the junctional zone, an effect abrogated in the restricted plus leptin group, which had a significant decrease in the labyrinth zone area compared with controls. Similarly, there were more significant differences in gene expression between placentas from control and restricted plus leptin mothers (1128 differentially expressed genes) than between placentas of control and restricted mothers (281 differentially expressed genes). We conclude that the presence of high concentrations of circulating leptin during food restriction disrupts the normal adaptive response of the placenta to reduced energy availability.