With an ever rising number of patients diagnosed with hypertension, the poor efficacy, compliance and tolerability of current medicines, and the apparent absence of new anti-hypertensive medications over the last 15 years there has been a major resurgence of interest in strategies focused on intervening directly with autonomic control mechanisms. Renal denervation, carotid sinus stimulation and deep brain stimulation are all examples and have all undergone trials in an attempt to curb the significant causal problem of increased sympathetic traffic to cardiovascular end organs. These strategies may all prove therapeutically useful in sub-cohorts of patients with drug-resistant high blood pressure. In this presentation, I will explore the carotid body as a potential novel target for regulating sympathetic outflow that may have considerable advantages including the ability to identify patients with pathological or hyperactive carotid bodies and to assess whether the intervention has been effective in reducing aberrant carotid body discharge as well as abating sympathetic traffic chronically. Ideally, any therapeutic intervention would be reversible, free from side effects and, importantly, would only remediate the pathology sparing physiological function. Using multiple models of hypertension and numerous animal species, and human patients, I will present our recent findings demonstrating the pathological role of purinergic receptors (specifically, P2X3) in the carotid body pertaining to conditions of autonomic imbalance and sympathetic activity excess. Using selective P2X3 receptor antagonists we may be able to provide a much needed approach for restoring carotid body physiology and autonomic homeostasis across a range of diseases including high blood pressure in which the sympathetic nervous system has become overactive.