Large randomised clinical trials have shown ACE inhibitors to improve survival after acute myocardial infarction (AMI). The precise mechanism underlying this benefit is not fully established, despite extensive research. There is also controversy with regard to the clinical use of these drugs, particularly the need for selection of patients prior to treatment and the timing of drug initiation and withdrawal for maximum benefit. Animal models of AMI used to assess drug effects are of limited value in understanding the mechanisms of benefit because they involve significantly different pathophysiology from that which occurs in humans. Here we propose that the benefit of ACE inhibitor therapy is largely confined, post-AMI, to those with evidence of left ventricular dysfunction clinically or on investigation, and suggest the continuing importance of treatment distant from the acute event. We argue that the beneficial effects are, at least in part, related to a reduction in the direct toxic effects of angiotensin II and catecholamines on cardiomyocytes resulting from the long term excess stimulation of the renin-angiotensin and sympathetic systems in these patients. Importantly, we believe that for some patients after AMI there is little or no benefit to be gained from treatment and that, in fact, careful analysis of the trials suggests that ACE inhibitors may be associated with adverse outcomes in some individuals. Finally, since ACE inhibitors also potentiate bradykinin and other peptides, their beneficial action may not simply be due to reducing the formation of angiotensin II. The proportion of the benefit that may be via bradykinin is difficult to assess, especially in humans. However, the advent of the angiotensin receptor antagonists has provided the opportunity to investigate this important issue.