The effects of the autonomic nervous system on malignant arrhythmias, particularly in the setting of ischemic heart disease, have been widely investigated and described. Specifically, it has been shown that while sympathetic hyperactivity is arrhythmogenic, an increased vagal activity often exerts a beneficial effect. New insights on the relationship between autonomic activity and sudden cardiac death have been obtained in conscious dogs in which a healed myocardial infarction, acute myocardial ischemia, and exercise are combined. In this chronic animal model it was shown that myocardial infarction reduces baroreflex sensitivity and heart rate variability (markers of vagal reflex and tonic activity to the heart) and that a depressed baroreflex sensitivity or a reduced heart rate variability after myocardial infarction indicate an increased risk for ventricular fibrillation. The validity of these experimental observations was confirmed in clinical studies in patients with a myocardial infarction. The protective effect of vagal activity was further confirmed in two experimental studies in which muscarinic stimulation, both electrically and pharmacologically induced, was able to prevent ventricular fibrillation during acute myocardial ischemia. These observations have led to new research directions. At the experimental level, the effect of Gi proteins activity blockade by pertussis toxin on the cardiac response to vagal activation is currently evaluated in conscious dogs. At the clinical level, the prognostic value after myocardial infarction of baroreflex sensitivity and of heart rate variability will be tested in a large, multicenter, prospective study.