With the majority of hypertensive patients on medication remaining hypertensive, new targets and a better understanding of blood pressure control are required. We believe an effective strategy would be to better understand central nervous control of circulation. We highlight progress in our understanding of brain control of cardiovascular autonomic outflows in homeostatic regulation of circulation, and the changes that occur with hypertension. We review evidence that correlates alterations of cardiovascular autonomic activity with the development of hypertension in animal models and humans. We comment on the response of the autonomic nervous system and its reflex control in hypertensives after exposure to antihypertensive agents. We address the possibility of a causative role of the autonomic nervous system in the development of hypertension. We summarize possible central nervous system mechanisms that may underpin the development and maintenance of high blood pressure. As some antihypertensive agents interfere with the reninangiotensin system, and may cross the blood-brain barrier, our attention focuses on central angiotensin II type 1 receptor–mediated intracellular signaling. Based on recent data, we conclude with a novel hypothesis for the etiology of hypertension that is consistent with the historical viewpoint of Cushing...