Oxygen (O2) free radicals are a potential teratologic threat to the foetal tissues and are known to be involved in the pathophysiology of common human pregnancy disorders such as miscarriage and pre-eclampsia. During the first two months of human gestation, the placenta surrounds the whole gestational sac, the villi contain only a few capillaries located mainly within the centre of the mesenchymal core, the trophoblastic layer is twice the thickness it will be in the second trimester, the foetal red cells are nucleated and the exocoelomic cavity (ECC) occupies most of the space inside the gestational sac. The ECC contains no oxygen transport system, but anti-oxidant molecules that may provide additional protection to the embryo from oxidative damage are present. Ultrasound and anatomical studies have also demonstrated that the intervillous circulation starts in the periphery of the placenta at around 9 weeks of gestation, and that it becomes continuous and diffuse in the entire placenta only after 12 weeks. Overall, these anatomical features provide indirect evidence that the architecture of the human first trimester gestational sac limits foetal exposure to O2 to what is strictly necessary for its development. These results are in agreement with the concept that the placenta and foetus develop in a physiologically low O2 environment and that its metabolism must be essentially anaerobic. Because of these anatomical arrangements, different nutritional pathways to those operating during most of pregnancy must serve the first-trimester foetus. Up to 9 weeks of gestation, foetal nutrition appears to depend on uterine glandular secretions that are delivered into the intervillous space, supplemented by maternal plasma proteins and other molecules that may percolate through the trophoblastic shell. These molecules diffuse through, or are transported by, the trophoblast of the villi and the chorionic plate into the ECC. From here they are absorbed by the secondary yolk sac (SYS), in which the extraembryonic circulation is probably first established. At the end of the first trimester, the SYS and two-thirds of the placental mass degenerate, and the ECC is progressively obliterated by the enlarging amniotic cavity. The trophoblastic plugs occluding the utero-placental arteries are gradually dislocated, allowing maternal blood to flow into the intervillous space, and the uterine glands involute. These major anatomical transformations modify considerably the spatial relationships between the maternal tissues and the developing embryo, and, consequently, the materno-embryonic exchange pathways. Overall the comparison of morphological features with physiological findings reveals that the architecture of the human first trimester gestational sac is designed to limit foetal exposure to oxygen to that which is strictly necessary for its development, and that during early pregnancy alternative nutritional pathways are in use. 2002 Published by Elsevier Science Ltd. Placenta (2002), 23, 000–000