Introduction: transfer of glucose across the human placenta is directly proportional to maternal glucose concentrations even when these are well above the physiological range. This study investigates the relationship between maternal and fetal glucose concentrations and transfer across the placenta. Methods: transfer of d-glucose, 3H-3-o-methyl-d-glucose (3H-3MG) and 14C-l-glucose across the isolated perfused human placental cotyledon was determined for maternal and fetal arterial d-glucose concentrations between 0 and 20 mmol/l. Results: clearance of 3H-3MG or 14C-l-glucose was not affected by maternal or fetal d-glucose concentrations in either circulation. Discussion: based on the arterial glucose concentrations and the reported KM for GLUT1, the transfer of d-glucose and 3H-3MG would be expected to show signs of saturation as d-glucose concentrations increased but this did not occur. One explanation for this is that incomplete mixing of maternal blood and the rate of diffusion across unstirred layers may lower the effective concentration of glucose at the microvillous membrane and subsequently at the basal membrane. Uncertainties about the affinity of GLUT1 for glucose, both outside and inside the cell, may also contribute to the difference between the predicted and observed kinetics. Conclusion: these factors may therefore help explain why the observed and predicted kinetics differ and they emphasise the importance of understanding the function of transport proteins in their physiological context. The development of a computational model of glucose transfer may improve our understanding of how the determinants of placental glucose transfer interact and function as a system