Beta-blockers are known to improve mortality post myocardial infarction and in chronic congestive heart failure where sympathetic drive to the heart is high. However, the release of additional sympathetic co-transmitters can have deleterious consequences for cardiac parasympathetic neurotransmission even in the presence of these medications. Stimulation of the cardiac vagus reduces heart rate, lowers myocardial oxygen demand, improves coronary blood flow and independently raises ventricular fibrillation threshold. Methods used to assess vagus function in humans have demonstrated that higher nerve activity is a protective prognostic indicator in several cardiovascular disease states. This presentation will discuss recent data demonstrating a direct action of the sympathetic co-transmitters neuropeptide-Y and galanin on the ability of the vagus to release acetylcholine (1, 2), as well a strong correlation between plasma neuropeptide-Y levels and coronary microvascular function in patients with ST-elevation myocardial infarctions being treated by primary percutaneous coronary intervention (3). Targeting neuropeptide-Y receptors pharmacologically may therefore be a useful therapeutic strategy both acutely during myocardial infarction and also during chronic heart failure. Such medications would be expected to act synergistically with beta-blockers and implantable vagus nerve stimulators to improve patient outcome.