The transport and metabolism of glutamine (GLN) and glutamate (GLU) during fetal development exhibit unique characteristics that clearly emphasize the importance of the interaction between the placenta and the fetal liver. GLN is delivered into the fetal circulation at a rate that is the highest of all the amino acids. In contrast, approximately 90% of fetal plasma GLU is extracted by the placenta. Conversely, the fetal liver has a large net output of GLU and a net uptake of GLN. We have studied the fluxes of GLU and GLN into and out of the placenta and fetal liver, as well as their interconversion in these organs, during late gestation in sheep. In the fetus, 45% of GLN carbon taken up by the liver exits as GLU; indeed, the production of GLU from GLN is large, approximately 3.7 micromol/(min.kg fetus), and accounts for virtually all of the GLU produced in the fetus. In contrast, only 6% of GLU carbon is converted to GLN in the placenta; most of the fetal plasma GLU taken up by this organ is converted to CO(2). Remarkably, placental GLU uptake accounts for >60% of the fetal plasma GLU disposal rate. In some respects, the net output of GLU from the liver in fetuses replaces the net hepatic glucose output that is characteristic of postnatal life. We also examined GLN and GLU fluxes in pregnant sheep during either dexamethasone-induced or spontaneous parturition. At parturition, a striking reduction in GLU output from the fetal liver occurred, leading to a fall in fetal arterial GLU concentrations and a marked decrease in placental GLU uptake. These changes were progressive as parturition advanced and correlated with a marked decrease in progesterone output from the pregnant uterus.