Coordinated maternal, fetal and placental responses to pregnancy are required to ensure a continuous delivery of nutrients to the developing organism. Oxygen can be viewed as one such nutrient since fetal growth is impaired under the conditions of chronic hypoxia present at high altitude (>2500 m), during severe maternal anemia or uteroplacental ischemia. Some 140 million persons live at high altitude worldwide and thus comprise the largest single group at risk for fetal growth restriction. Of interest is that not all human populations are equally susceptible to altitude–associated fetal growth restriction. Comparing literature observations for some 4 million births at 0 – 5000 m, multi–generational Tibetan and Andean populations demonstrate less altitude–associated reduction in birth weight than Europeans or Han (Chinese) who have resided there for <1 or only a few generations. Our current studies in Bolivia use this experiment of nature to test the hypothesis that genetic factors (a) influence susceptibility to altitude-associated fetal growth restriction, (b) act on maternal uteroplacental and systemic vascular adaptations to pregnancy which determine uteroplacental blood flow, and (c) involve genes which regulate and/or are regulated by hypoxia–inducible factors (HIFs). In 3538 prenatal, labor and delivery, and newborn records at 300–4100 m from both public and private facilities in Bolivia, there is less altitude–associated fetal growth restriction in babies born to Andean vs. European–surnamed parents. Birthweight reductions are intermediate in mestizo (“mixed”)–surnamed infants. A more refined classification using 5 ancestry groups for the high–altitude deliveries suggest that the protective effect of Andean ancestry is “dose–dependent”. To determine whether maternal oxygen delivery to the uteroplacental circulation differs in women of Andean vs. European ancestry, we conducted physiological studies at 20, 30 and 36 weeks of pregnancy as well as when nonpregnant (3 mo postpartum) in 50 Andean and 25 European women residing at 3200–4100 m. Both groups show similar increases in ventilation and blood volume with pregnancy, but O2 content falls slightly as the result of greater plasma volume than red cell mass expansion. There is less pregnancy–associated increase in uterine artery diameter in the European than Andean women with the result that calculated uterine artery blood flow and O2 delivery is lower in the European women from pregnancy wk 20 until term. Preliminary measurements of the products of HIF–targeted genes indicate that Andean women have lower levels of the circulating vasoconstrictor endothelin–1 (EDN) during pregnancy than European women. Initial genomic studies using single nucleotide polymorphisms (SNPs) suggest that a considerable proportion (44%) of the differences between Andean populations and low–altitude controls resides near HIF–targeted genes. Future studies are planned for deciding whether genetic factors influence susceptibility to hypoxia–induced fetal growth restriction and the particular genes or genomic regions involved. In relation to developmental programming, studies at high altitudes raise questions as to whether hypoxia “programs” developmentally and if so, what are the relative contributions of genetic vs. developmentally–acquired influences on the programmed phenotype.