Available information indicates that about 78 new molecules belonging to the class of angiotensin converting enzyme (ACE) inhibitors are under investigation, and that at least 11 or 12 of the newer ACE inhibitors will be available for clinical use. The newer ACE inhibitors can be classified, according to the zinc ion ligand of ACE, into 3 main chemical classes: sulfhydryl-, carboxyl- and phosphoryl-containing ACE inhibitors.All the newer sulfhydryl-containing ACE inhibitors differ from captopril since they are prodrugs, and among them alacepril and probably moveltipril (altiopril, MC 838) are convertedin vivoto captopril. When compared with captopril, they show a slower onset and a longer duration of action, and obviously the same route of elimination. Zofenopril, a prodrug that is convertedin vivoto the active diacid, shows a greater potency, a similar peak time and a longer duration of action than captopril and, unlike captopril, partial elimination through the liver.The newer carboxyl-containing ACE inhibitors are prodrugs which are convertedin vivoto active diacids. Like enalaprilat, they are excreted via the kidney; the exception is spirapril, which is totally eliminated by the liver. Compared to enalapril, benazepril shows an earlier peak time and a slightly shorter terminal half-life, cilazapril and ramipril have an earlier peak time and even longer terminal half-life, perindopril shows similar peak time and terminal half-life, while delapril, quinapril and spirapril show an earlier peak time and a shorter half-life. The phosphoryl-containing ACE inhibitors belong to a new chemical class. Fosinopril is a prodrug which is converted to the active diacidin vivo, shows a relatively late peak time, a long terminal half-life, and is eliminated partially by the liver. SQ 29852, the only newly developed ACE inhibitor which is not a prodrug, seems to be more effective than captopril, with a much longer lasting effect and elimination through the kidney.When the differences in potency between these drugs are compensated by dosage adjustment, all the newer ACE inhibitors are expected to exert a similar amount of inhibition of circulating ACE, and therefore to inhibit to a similar extent the generation of circulating angiotensin II and the breakdown of bradykinin. Obviously they may differ in timing and the duration of circulating ACE inhibition according to their pharmacokinetic properties. With regard to the possibility that they may stimulate prostaglandin synthesis, it is suggested that this action, which does not seem to be specific to this drug class, plays only a minor role in their antihypertensive action; the hypothesis that the sulfhydryl group exerts an additional stimulating action remains to be proved.Experimental data, however, indicate that ACE inhibitors are able to inhibit tissue ACE, that each drug may differ in the amount and duration of ACE inhibition in different tissues, and that tissue bioavailability seems to be the major determinant of these differential effects. These findings raise the theoretical possibility that newer ACE inhibitors might be designed with preferential affinity to various organs, with different therapeutic profiles.As with the systemic humoral effects, it is expected that all the newer ACE inhibitors will exert similar systemic haemodynamic actions. However, the question of whether the different tissue penetration and/or inhibition of the tissue renin-angiotensin system will differentiate the newer ACE inhibitors in terms of regional haemodynamics remains to be answered.The usefulness of the newer ACE inhibitors in the treatment of hypertension and of congestive heart failure is under clinical investigation. Whether these drugs can offer the same or additional advantages or disadvantages as their parent drugs is still in the future.