Several cohort studies have shown that increasing heart rate (HR) is a predictor of cardiovascular mortality in apparently healthy subjects, independent of several other potential coronary risk factors. Increased resting HR is also a well-known negative prognostic sign in patients with acute myocardial infarction (MI) and in those with heart failure. The predictive value of HR in MI patients extends at long-term follow-up, is independent of most clinical parameters, including left ventricular function, and seems maintained in the modern era of aggressive reperfusion treatment. In accordance with these data, numerous clinical studies have demonstrated that Beta-blockade, which decreases HR, has significant favorable clinical effects in patients with a history of acute MI or heart failure. Although the unfavorable prognostic effect of HR may reflect the deleterious effect of a sympathovagal imbalance, characterized by sympathetic predominance and vagal depression, several data suggest that HR may by itself cause negative effects on cardiovascular function, inducing an increase in cardiac work and myocardial oxygen consumption and a reduction of the diastolic time, with a reduction of time of myocardial blood supply, both conditions favoring the development of myocardial ischemia, besides facilitating arrhythmias in myocardial ischemic areas, by reentry mechanisms. Thus, a reduction of HR might have direct beneficial clinical effects, as also suggested by experimental findings.