THE HUMAN BRAIN makes up only 2% of body weight, although it consumes more than 20% of oxygen and glucose at rest, with almost all adenosine triphosphate within the brain being produced by oxidative metabolism of glucose (3). In addition to a great need for substrate provision and by-product clearance, the metabolic circumstances in the brain are compromised by a limited intracellular capacity for energy storage. These two characteristics, combined with the paramount importance of brain function compared with other end organs, necessitate precise regulation of cerebral blood flow (CBF). Regulation of CBF is achieved through several factors including metabolic, myogenic, and neurogenic control, as well as systemic blood flow (10). Specifically, the primary controllers of CBF are partial pressure of arterial CO 2 , cerebral metabolism, cardiac output, and the autonomic nervous system (11,19). The role of the autonomic nervous system has been particularly difficult to assess due to a number of factors stemming from the redundant mechanisms at play involving a combination of neurovascular coupling, arterial blood gases, and systemic blood flow (19).The role of the sympathetic arm of the autonomic nervous system has been particularly suspected to play a role in CBF regulation (7), as this system is crucial for regulating blood flow/vascular resistance systemically. However, the role the sympathetic nervous system (SNS) plays in regulating the cerebrovasculature has been thought to be limited to providing baseline tonic influence (lowering resting CBF) and then also by buffering CBF, albeit only at very high levels of perfusion pressure (1, 6). Understanding how and when the SNS influences CBF regulation not only has basic exploratory science importance but also will affect our understanding of how a number of clinical conditions impact cerebrovascular health, particularly autonomic disorders. A small number of studies have attempted to assess the role of the SNS in actively regulating CBF in humans; however, these studies have focused on SNS control during large perturbations in blood pressure (i.e., 40-mmHg repetitive swings or 30-mmHg rapid decreases), which obviates direct translation to the real world setting, as well as utility in clinical populations (5, 9). Furthermore, these studies have relied on transfer function analyses, which assumes that perfusion pressure is the only factor influencing CBF and that perfusion pressure and CBF interactions are linear and stationary, a circumstance that is almost certainly not possible considering the multifactorial regulation of CBF (5,20). Lastly, the majority of previous studies evaluating the SNS influence on CBF regulation have used phentolamine as their drug of choice, which creates problems for interpretation, as this is a nonspecific ␣ 1 -and ␣ 2 -blocker with agonistic effects of muscarinic and histamine receptors, factors that can directly influence CBF regulation themselves (4, 15).In the current issue of the American Journal of PhysiologyHeart and Circulatory ...