The brain can withstand only very short periods of ischemia because neurons produce ATP almost entirely by oxidative metabolism. Without oxygen, energy-dependent processes stop causing irreversible cellular injury. Therefore, cerebral blood flow must be maintained to ensure oxygen delivery and removal of the products of metabolism. The regulation of the cerebral circulation is an intricate and critical process that relies on the complex and interacting influences of the cardiovascular, respiratory, neural, and local metabolic systems. These physiologic systems act in complex and interacting ways to maintain an adequate cerebral blood flow by altering arterial, intracranial, and venous pressures. This is achieved by multiple mechanisms. For example, cerebral autoregulation is the response of the cerebral vessels to changes in arterial blood pressure. It is well documented that a decrease in systemic arterial blood pressure causes dilatation of the cerebral vessels and that, conversely, an increase in systemic arterial blood pressure causes vasoconstriction of the cerebral circulation. Changes in cerebral vascular tone are also mediated by putative constricting and dilating substances, and cerebral blood flow is tightly coupled with regional brain metabolism. These vasoactive substances may be supplied to the vessels via the bloodstream [e.g., arterial partial pressure of carbon dioxide (PaCO2), produced locally (adenosine, nitric oxide, potassium)] or reach the vascular smooth muscle through direct autonomic innervation (acetylcholine, norepinephrine). Unique anatomical features, including the rigid skull, are also important considerations in the control of cerebral blood flow. In this chapter, we briefly discuss the major factors regulating cerebral blood flow including important anatomical features for a functional understanding of the regulation of the cerebral circulation.