Understanding the influence of oxygen (O2) availability on cerebral blood flow (CBF) and brain metabolism is an essential step toward a better understanding of brain energy homeostasis and has obvious clinical implications. In the context of the influence of O2 availability on human CBF regulation, the following three key theses are highlighted: 1) in every form of hypoxemia (e.g., prolonged apnea, and conditions of acute and chronic exposure to normobaric and hypobaric hypoxia) in healthy humans, elevations in CBF are intimately matched to compensate for reductions in oxygen content in order to precisely maintain cerebral oxygen delivery; 2) studies of hemodilution, and those in patients with anemia and polycythemia, all support the notion that oxygen content has an independent influence on CBF, whereby stable cerebral oxygen delivery is maintained; and 3) the molecular mechanisms underpinning the regulation of CBF during changes in O2 are multifactorial but chiefly involve prostaglandin and adenosine activity, and activation of ATP-sensitive potassium channels with hypoxia and increases in reactive oxygen species with hyperoxia. The emerging picture supports the role of oxygen delivery as a biological regulator of CBF in order to tightly regulate tissue oxygenation of the brain during changes in oxygen content originating from alterations in O2 tension, hemodilution, and anemia.