It is sobering to recall that, despite much basic research and many small and large clinical trials, we still do not know how angiotensin-converting enzyme inhibitors work. This is true both in terms of their fundamental mode of action at a cellular level as well as in the patient in the clinical setting. New pharmaceutical compounds such as renin inhibitors, angiotensin II receptor antagonists and aldosterone antagonists are bringing new insights not only into the importance of different components of the renin-angiotensin-aldosterone system in heart failure but also into the mode of action of angiotensin-converting enzyme inhibitors. This manuscript also provides a brief update on the organization of the renin-angiotensin-aldosterone system and other angiotensin-II-forming pathways with special relevance to heart failure. Data on the potential relevance of genetic polymorphisms of the renin-angiotensin-aldosterone system are discussed. Possibly the single most important observation in clinical cardiovascular medicine in 1995 was the reporting of a highly significant interaction between angiotensin-converting enzyme inhibitors and aspirin on mortality in patients with ventricular dysfunction with or without heart failure. This has called into question the safety of aspirin use in heart failure.