In this review, we have considered interrelationships between blood flow and oxygen requirements of the body during fetal and neonatal development. During fetal life, blood is oxygenated in the placenta and returns to the fetus through the umbilical vein. The ductus venosus serves as a bypass of umbilical venous blood from the hepatic microcirculation. Preferential streaming of blood in the inferior vena cava facilitates delivery of well-oxygenated ductus venosus blood to the brain and heart. During fetal stress of hypoxia or umbilical cord compression, flow through the liver and ductus venosus is modified to facilitate oxygen delivery to the fetal body and local organ vascular responses, and to maintain blood flow and oxygen delivery to vital organs, such as the brain, heart, and adrenal gland. During fetal life, immaturity of the fetal myocardium accounts for limited ability for cardiac output to be augmented when ventricular filling pressure is increased above the resting level; yet immediately after birth, cardiac output increases dramatically. Experimental evidence points to an important role of prenatal thyroid hormone in maturation of the myocardium for postnatal requirements. In association with the increase in oxygen requirements after birth, cardiac output increases, but because resting requirements for blood flow are high, there is a limited ability for cardiac output to be increased further. With postnatal development, cardiac output requirements in relation to body weight decrease, partly in parallel with reduced oxygen requirements related to body weight, but also as a result of rightward shift of the oxygen dissociation curve as fetal hemoglobin is replaced by adult hemoglobin. Understanding the circulatory and metabolic changes that occur in the perinatal period and the mechanisms of response to stress is important in management of the newborn infant with cardiorespiratory distress.