Angiotensin-converting enzyme inhibitors are extensively used to improve clinical outcome of patients with several cardiovascular diseases. Zofenopril proved to be very effective in patients with coronary artery disease and myocardial infarction, thanks to its unique effective mechanism of action for improving blood pressure control, left ventricular function and myocardial ischemia burden, as well as angiotensin-converting enzyme inhibition. The SMILE project involved more than 3500 patients with coronary artery disease and demonstrated that zofenopril treatment may reduce mortality and morbidity in patients with myocardial infarction, also when combined with acetyl salicylic acid and to a greater extent than lisinopril and ramipril. In addition, the results of the SMILE-ISCHEMIA study have demonstrated an interesting anti-ischemic effect of zofenopril, and these properties largely contribute to the overall clinical benefit of the drug. The effects of zofenopril on blood pressure control and cardiovascular protection clearly support its primary role for prevention and treatment of cardiovascular diseases.