The antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitors cannot be fully explained by their actions on the circulating renin-angiotensin system (RAS). Agents such as captopril or enalapril maintain efficacy during long-term therapy even when plasma concentrations of converting enzyme or angiotensin II are not fully suppressed. Components of the entire RAS exist at several sites, thereby making it possible for drugs to produce effects at extracirculatory locations. An ACE inhibitor such as quinapril that has a comparatively short plasma concentration half-life binds strongly to plasma ACE as well as to ACE in key tissues including artery wall, heart, and kidney. The effects of ACE inhibition on the tissue RAS are of potential importance in fully explaining the blood pressure-lowering effects of these drugs. ACE inhibitors might also reduce blood pressure by blocking nonhemodynamic actions of angiotensin II. They affect vascular properties by increasing compliance of arteries and they act on baroreceptors and central regulatory mechanisms. Furthermore, ACE inhibitors affect other neuroendocrine systems, including aldosterone, kinins, and prostaglandins; attenuation of sympathetic activity can contribute further to their antihypertensive properties. Actions independent of circulating renin effects do not necessarily require plasma ACE inhibition throughout a 24-hour period. Sustained antihypertensive effects by drugs with short durations of plasma ACE inhibition give credibility to therapeutic targets beyond the circulating RAS.