Phenylephrine is a direct-acting, predominantly α(1) adrenergic receptor agonist used by anesthesiologists and intensivists to treat hypotension. A variety of physiologic studies suggest that α-agonists increase cardiac afterload, reduce venous compliance, and reduce renal bloodflow. The effects on gastrointestinal and cerebral perfusion are controversial. To better understand the effects of phenylephrine in a variety of clinical settings, we screened 463 articles on the basis of PubMed searches of "methoxamine," a long-acting α agonist, and "phenylephrine" (limited to human, randomized studies published in English), as well as citations found therein. Relevant articles, as well as those discovered in the peer-review process, were incorporated into this review. Phenylephrine has been studied as an antihypotensive drug in patients with severe aortic stenosis, as a treatment for decompensated tetralogy of Fallot and hypoxemia during 1-lung ventilation, as well as for the treatment of septic shock, traumatic brain injury, vasospasm status-postsubarachnoid hemorrhage, and hypotension during cesarean delivery. In specific instances (critical aortic stenosis, tetralogy of Fallot, hypotension during cesarean delivery) in which the regional effects of phenylephrine (e.g., decreased heart rate, favorable alterations in Q(p):Q(s) ratio, improved fetal oxygen supply:demand ratio) outweigh its global effects (e.g., decreased cardiac output), phenylephrine may be a rational pharmacologic choice. In pathophysiologic states in which no regional advantages are gained by using an α(1) agonist, alternative vasopressors should be sought.