Clinical trials in diet and cancer have special problems. We distinguish between a nutritional supplementation and a dietary intervention trial. Since the latter involves a lifestyle modification the intervention requires more careful planning. To illustrate, the method used to reduce the fat intake of subjects in the Women's Health Trial is described. Any clinical trial should satisfy three basic criteria before initiation: plausibility of hypothesis, feasibility, and justifiable cost. In diet and cancer the plausibility of a hypothesis is often controversial. Our conventional reliance on evidence from case-control and cohort studies for judging the plausibility of dietary hypotheses may be misplaced. Errors in the assessment of individuals' diets and the difficulties of separating the effects of highly correlated dietary variables impose severe limitations on the ability of these studies to elucidate the possible effects of diet on cancer incidence. It is therefore unlikely that a consistent pattern of results will be found. Randomized intervention trials, although expensive, have several advantages over analytic epidemiological studies. For example, whereas dietary assessments are required in epidemiological studies to establish a relationship, in intervention trials they are needed only to explain the relationship. We conclude that there is a serious need for reconsidering the relative importance of evidence from various kinds of epidemiological studies relating to diet and cancer.