Defects in all the trophoblast-differentiating pathways--endovascular, interstitial and chorionic villous--play a role in the pathogenesis of early-onset intra-uterine growth restriction (IUGR). There are two types of extravillous trophoblast: endovascular trophoblast, that forms the definitive placenta by occlusion of the spiral arteriole at the implantation site, and interstitial extravillous trophoblast, responsible for the anatomical erosion of the distal spiral arteriole and the secretion of angiogenic and vasodilator signals to improve uterine blood flow. Defective endovascular erosion may render the basal plate inadequate to meet the demands of the fetus. Failed interstitial invasion of spiral arterioles could lead to failure of local angiogenic and systemic cardiovascular adaptation signals that could be the underlying basis for early-onset IUGR and pre-eclampsia. As debate persists regarding the relative importance of cord, stem and terminal villous pathology, the study of factors controlling trophoblast turnover from immature intermediate villi to conductance stem villi and gas-exchanging terminal villi, translation of our knowledge from mouse placental genetics into human placental development, and defining causes of thrombo-occlusive damage to the placenta would help our understanding of the pathophysiology of early-onset IUGR.