Many organs contain neural sensors detecting the chemical milieu. These sensors include those sensing oxygen and/or blood perfusion. They feed back afferent signals to the central nervous system triggering reflex responses that bring about appropriate homeostatic adjustment. Typically, this involves activation of the sympathetic nervous system to raise perfusion pressure in an attempt to restore adequate tissue oxygenation and blood flow within the organ from which the afferent signal originated. Hypertension is a condition characterized by high vascular resistance, elevated sympathetic activity, T-lymphocyte vascular infiltration and inflammation, and vascular hypertrophy. These symptoms all hamper organ blood flow and oxygenation. Our working hypothesis is that the organs that are most sensitive to restriction in blood flow and reduced oxygenation (i.e. hypoperfusion) are likely to be critical for life and contribute greatest to reflexly evoked increases in sympathetic activity and hypertension. These organs are the brain and carotid body chemoreceptors. After all, carotid body function in ensuring adequate oxygenation of the brain may be the most important one they possess. The relative contribution of brainstem hypoperfusion, carotid body activation and the interaction between these organs in hypertension will be discussed. My presentation will include reciprocating translational studies between animal models with hypertension and hypertensive patients. I will present data revealing elevated cerebral vascular resistance in hypertension that occurs prior to the onset of the hypertension. I will report on a novel intra-cranial detector system that when activated by cerebral hypoperfusion produces sustained hypertension. As a putative transduction mechanism for the detection of cerebral hypoperfusion, and resultant sympathoexcitation, I will discuss the role of TRPV4 channels. An issue with cerebral perfusion in hypertension may be due to a paucity of parasympathetic vasodilator fibre innervation and poor functional hyperaemic responses: I shall provide evidence describing such changes. I will also show that carotid body chemoreceptors not only have heightened reflex sensitivity but also tonicity in hypertension. Although it is well known that repeated stimulation of the carotid body triggers hypertension and increases in sympathetic nerve activity, we have found that this is, in part, mediated via an adrenomedullin mediated mechanism in the rostral ventrolateral medulla and enhanced central respiratory-sympathetic coupling. Our recent results show that hypertension and excessive sympathetic nerve activity can be alleviated by removing carotid body afferent feedback, which reduces the excitatory synaptic coupling of respiratory cells innervating pre-sympathetic motoneurones. Based on these results, I will discuss novel therapeutic interventional approaches to treat drug-resistant hypertension in humans.