The cardiovascular (CV) system is complex, which comprises of the heart and blood vessels. Diseases, such as hypertension, congestive heart failure, angina pectoris, atherosclerosis, rheumatic heart, arrhythmias and vascular inflammation may afflict the CV system. The CV drugs attempts to treat this variety of diseases are in fact targeting the heart and blood vessels in multiple ways. In 1939, it was discovered that renin itself did not cause rise in blood pressure, but was an enzyme, which catalyzed the formation of the substances that were responsible for vasoconstriction, namely, angiotensin (Ang) I and II. Compounds that block the action of Ang II by preventing Ang II from binding to Ang II receptors on blood vessels and thus responsible for reducing the blood pressure are named “angiotensin receptor blockers” (ARBs). Functions beyond hypertension control are studied. The renin-angiotensin cascade and angiotensin II receptor subtypes, development of saralasin, and development from losartan to other drugs are discussed. The ARB controversy—myocardial infarction, cardiovascular protection—a breakthrough for high-risk patients, the new challenge—ARBs as cancer risk factor, time line of landmark trials with ARBs, and ARBs under development are described.