The actions of ACE inhibitors at the tissue level (brain, heart, blood vessels) and their interference with the automatic nervous system through central and peripheral actions may, under certain conditions, be more important than inhibition of the hormonal circulating plasma angiotensin (ANG) II. Recent clinical and experimental studies and new insights into the molecular biology of the renin-angiotensin system support this view, in particular gene expression of renin and angiotensin in tissues of the cardiovascular system. These findings have implications not only for understanding the pharmacokinetics and pharmacodynamics of ACE inhibitors, but also for their therapeutic use.