Until two decades ago nitroglycerin was contraindicated in acute myocardial infarction (MI). Studies in the canine model demonstrated that low-dose intravenous (i.v.) infusion, carefully titrated to decrease mean blood pressure by 10% but not below 80 mmHg, during early stages of acute MI produced marked reduction of left ventricular (LV) preload, improvement in regional perfusion, and limitation of infarct size and remodeling. However, more i.v. nitroglycerin to decrease blood pressure further resulted in a paradoxical J-curve effect, with hypoperfusion and increased infarct size. Clinical studies have confirmed that low-dose i.v. nitroglycerin infusion for the first 48 hours after acute MI is safe, not only for improving performance in LV failure, but also for limiting ischemic injury, infarct size, remodeling, and infarct-related complications, including deaths in-hospital and up to 1 year. Recent studies suggest that more prolonged therapy with nitrates spanning the healing phase of acute anterior Q-wave MI can further limit LV remodeling and preserve function. Preliminary results of the recently completed ISIS-4 megatrial suggest, however, that long-term nitrate in patients with suspected MI in the 1990s does not improve survival significantly.