Severe autonomic failure occurs in approximately 1 in 1,000 people. Such patients are remarkable for the striking and sometimes paradoxic responses they manifest to a variety of physiologic and pharmacologic stimuli. Orthostatic hypotension is often the finding most commonly noted by physicians, but a myriad of additional and less understood findings also occur. These findings include supine hypertension, altered drug sensitivity, hyperresponsiveness of blood pressure to hypo/hyperventilation, sleep apnea, and other neurologic disturbances. In this article the authors will review the clinical pathophysiology that underlies autonomic failure, with a particular emphasis on those aspects most relevant to the care of such patients in the perioperative setting. Strategies used by clinicians in diagnosis and treatment of these patients, and the effect of these interventions on the preoperative, intraoperative, and postoperative care that these patients undergo is a crucial element in the optimized management of care in these patients.