The fetus has the extraordinary capacity to respond to stress during development, which, in a large part, is mediated by the hypothalamo- pituitary-adrenal (HPA) axis. Hypoxia represents a significant risk to fetal homeostasis and can occur in a wide range of settings including maternal smoking, preeclampsia, preterm labor and high altitude. To study fetal adaptation to chronic, gestational hypoxia, we developed a model of high-altitude, long-term hypoxia (LTH) in pregnant sheep. We discuss the role of LTH on the HPA axis and potential programming of adaptive responses. LTH causes significant activation of the hypothalamic paraventricular nucleus (PVN) and anterior pituitary. In marked contrast, there is an adaptive inhibition in the adrenal, thus balancing the potentially maladaptive centrally mediated responses to LTH. Additionally, we discuss effects of LTH on adipose tissue development. LTH enhances leptin production, which in turn has a regulatory role on the adrenal cortex. Importantly, LTH also has a significant impact on programming of adipose tissue function. Together, our studies show that LTH induces a number of adaptive responses in the ovine fetus. Although they may be beneficial during fetal life, these adaptations could prove to be deleterious in the postnatal period and adulthood.