The recent history of randomized controlled trials in the prevention of ischaemic heart disease (i.h.d.) is considered. In 1970, it seemed that little could be done to prevent recurrence of the disease and there was almost no information on the potential for preventing its onset. Over the past decade, this rather pessimistic view has changed to one of guarded optimism. Yet there are still no drug regimes that command general support. One reason for the inconclusive results of recent trials may have been the assumption that myocardial infarction and sudden death share the same pathology. Another reason is the diversity of pathogenetic mechanisms and prognoses in i.h.d. Many patients probably stand little chance of benefiting from a particular drug either because it affects mechanisms other than those responsible for their disease or because their prognosis, excellent or hopeless, is unlikely to be influenced whatever treatment they receive. It is consequently difficult to ensure reasonable chances of demonstrating benefits in those who may really stand to gain. A tendency for pharmacological information to become available during or after a large trial, rather than beforehand, has added to the difficulties. Despite all their problems, randomized controlled trials remain the only way of testing drugs for the prevention of arterial disease. Suggestions are made for increasing the chances of clear results in future trials and of reaching the stage of benefit demonstrated sufficiently convincingly to form a basis for clinical practice. These suggestions include the use of factorial designs enabling the evaluation of more than one drug in a particular trial and the development of methods for selecting homogeneous groups of patients.