High levels of sympathetic drive in several cardiovascular diseases including post myocardial infarction, chronic congestive heart failure and hypertension are reinforced through dysregulation of afferent input and central integration of autonomic balance. However, recent evidence suggests that a significant component of sympathetic hyperactivity may also reside peripherally at the level of the post-ganglionic neuron. This has been studied in depth using the animal model of genetic essential hypertension, the spontaneously hypertensive rat, where larger neuronal calcium transients, increased release and impaired re-uptake of norepinephrine in neurons of the stellate ganglia lead to a significant tachycardia even before hypertension has developed. The release of additional sympathetic co-transmitters during high levels of sympathetic drive can also have deleterious consequences for peripheral cardiac parasympathetic neurotransmission even in the presence of beta-adrenergic blockade. Stimulation of the cardiac vagus reduces heart rate, lowers myocardial oxygen demand, improves coronary blood flow and independently raises ventricular fibrillation threshold. Recent data demonstrates a direct action of the sympathetic co-transmitters neuropeptide-Y (NPY) and galanin on the ability of the vagus to release acetylcholine and control heart rate. Moreover, there is as a strong correlation between plasma NPY levels and coronary microvascular function in patients with ST-elevation myocardial infarction being treated with primary percutaneous coronary intervention. Antagonists of the NPY receptors Y₁ and Y₂ may be therapeutically beneficial both acutely during myocardial infarction, and also during chronic heart failure and hypertension. Such medications would be expected to act synergistically with beta-blockers and implantable vagus nerve stimulators to improve patient outcome.