Blockade of the renin-angiotensin system (RAS) plays an important role in the prevention and correction of cardiovascular diseases. Agents that block the RAS such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are major in this league. There have been numerous clinical trials looking at the use of ACEIs and ARBs in hypertension, heart failure (HF), and other special population who remain at high risk for cardiovascular and cardiometabolic abnormalities. Overall, ACEIs are the first line agents, recommended for high cardiovascular risk patients and are supported suitably by worldwide therapeutic guidelines including class IA recommendation from American College of Cardiology (ACC)/American Heart Association. These recommendations are based on, large body of clinical results which overall supports ACEIs in reducing mortality, MI, stroke, and new-onset congestive heart failure, and their unique cardioprotective benefits in patients with diabetes, independent of coexistent atherosclerosis and concomitant nephropathy. Although, theoretically, ARBs offer improved blockade of the RAS system than ACEIs, their relative effectiveness in the treatment of HF and other comorbid cardiovascular conditions remains controversial as evident from clinical trial and meta-analysis results which shows that ARBs are not as effective in reducing mortality, rate of hospitalisation, prevention of nephropathic progression, etc. The results from the latest ONTARGET 'non-inferiority' trial has further elucidated the fact that ARBs are no better than ACEIs at reducing fatal and non-fatal cardiovascular events including MI and CV death. Although theoretically, combination of ACEIs and ARBs is an attractive therapeutic option as none of them block RAS completely, but it may also open the gate for supplementary collection of adverse events as has been evidenced in recent trials. Although, there are no data at present to precisely suggest the efficacy differences between all available ACEIs, there are trials which support that ramipril, a long acting ACEI with good tissue penetration, potent long-lasting inhibition of ACE may not be applicable to other available ACEIs. Ramipril also specifically reduces major adverse coronary and cerebrovascular events in post MI patients when compared to other ACEIs or placebo. When clinicians are faced with the choice of using either an ACEI or an ARB in high-risk patients, they should be mindful of the unique differences between each class of medication, particularly with respect to MI and CV death, and also the range of indications, cost and individual convenience.