The human placental circulation is crucial to providing nutrients to, and removing waste products from, the developing fetus. This vasculature comprises an intricate system of arteries and veins with vasoactive potential. In the villous tree, solutes are exchanged between placental capillaries and maternal blood via the syncytiotrophoblast epithelial cell layer. The venous system emanating from the capillaries transports blood, enriched in oxygen and nutrients from the maternal circulation, to the fetus. De-oxygenated blood exiting the fetus is returned by the umbilical artery, surface chorionic plate arteries and stem villi arteries to the villous capillary system for removal of waste products and re-oxygenation across the syncytiotrophoblast. Tone regulation throughout this vascular tree is an important determinant of fetal nutrient status impacting upon fetal growth and well-being. Intrauterine growth restriction (IUGR) in pregnancy, for example, is associated with impaired placental blood flow and significant infant morbidity and mortality as well as increased cardiovascular disease risk in later life. The need to understand the mechanisms of tone regulation of human placental vessels is therefore clear and makes the relative paucity of data to date somewhat surprising. Additionally, the lack of innervation of the human placenta presents an unique opportunity to consider how vascular tone may be modulated in the absence of central neuronal input. Consequently, we have embarked upon studies to investigate the structure and function of arteries and veins isolated from placentae of late term pregnant women. These have uncovered several features key to the placental vascular system that are noteworthy. Firstly, consistent with the placenta being an organ of low pressure and oxygenation, maximal agonist responsiveness of chorionic plate arteries is achieved at intralumenal pressures (or equivalent isometric stretches) and perfusate oxygenations of only ~25mmHg and ~7%, respectively (Wareing et al. 2006). Simultaneous measurements of [Ca²⁺]_i and tone in these intact arteries, coupled with studies of α-toxin-permeabilised vessels, illustrates that receptor-coupled agents, including endothelin-1, U44619 (a thromboxane mimetic) and sphingosin-1-phosphate (S1P), enhance tone via a prominent Ca²⁺-sensitisation of force (Wareing et al. 2005; Hemmings et al. 2006). In the case of S1P this is almost completely ablated by the Rho-associated kinase inhibitor Y27632; thromboxane receptor stimulation, in contrast, is only partly ROK-dependent indicating the capacity to invoke multiple Ca²⁺-sensitising signalling pathways. Electron microscopic examination of these arteries has also established unusual ultrastructural features including (i) an absence of internal elastic lamina and (ii) a paucity of smooth muscle sarcoplasmic reticulum (Sweeney et al. 2006). The former finding may contribute to differences in vasomotor oscillations evident in comparisons of placental and maternal arteries. The significance of the latter observation for placental vessel Ca²⁺ homeostasis remains to be established but could reflect the aforementioned reliance on prominent agonist-mediated Ca2+-sensitisations of tone. Secondly, although our preliminary structural data points to chorionic plate veins having fewer smooth muscle cell layers per cross-sectional area than arteries, the maximum constrictive forces are almost comparable (Wareing et al. 2003; Wareing et al. 2006). Similar to arteries, this is accomplished at the low pressures and oxygenations approximating that anticipated in vivo. Thirdly, our own evidence, and that in the literature, for a substantial agonist-mediated endothelial-dependent vessel relaxation is often elusive and certainly contentious. This is perhaps surprising given that placental endothelial cells are not separated from the underlying smooth muscle by a broad laminar structure as in maternal arteries. Vessel site is perhaps pertinent here; for example, the ability of S1P to effect NO-mediated dilatory influences may vary between chorionic plate and stem villi arteries (Hemmings et al. 2006). These studies of isolated human placental blood vessels indicate that there are several structural and functional features that distinguish them from adult systemic arteries and veins. Much further work is required to firmly establish how the intracellular, and intercellular, structural specialisations may relate to the signalling intricacies that regulate tone in both arteries and veins of the human placenta. This will be aided by consideration of how the vasculature is remodelled (i) from early to late pregnancy and (ii) in situations of compromised placental blood flow such as IUGR.