Orexin, the arousal peptide, originates from neurons located in an area of the dorsal hypothalamus well known for integrating defense responses and their cardiovascular component. Orexin neurons, which are driven in large part by the limbic forebrain, send projections to many regions in the brain, including regions involved in cardiovascular control, as far down as sympathetic preganglionic neurons in the spinal cord. Central injections of orexin evoke sympathetically mediated cardiovascular responses. Conversely, blockade of orexin receptors reduce the cardiovascular responses to acute stressors, preferentially of a psychological nature. More importantly, lasting upregulation of orexin signaling can lead to a hypertensive state. This can be observed in rats exposed to chronic stress as well as in strains known to display spontaneous hypertension such as the spontaneously hypertensive rat (SHR) or the hypertensive BPH/2J Schlager mouse. Thus, there is a link between orexin, stress and hypertension, and orexin upregulation could be a factor in the development of essential hypertension. Orexin receptor antagonists have anti-hypertensive effects that could be of clinical use.