The inhibition of cancer by calorie restriction was discovered over 50 years ago. By 1950 it had been well characterized and there existed sufficient data to propose a mechanism of action. For reasons that remain unclear, but are probably related to the perception of the calorie restricted rodent as "small" and the ad libitum feeding regimen as more "normal," the concept of calorie restriction has been largely ignored by investigators after this time. Hence, despite the fact that calorie restriction is one of the oldest, best-documented, and most effective ways known to reduce cancer risk in rodents, it has had little impact on modern cancer research. In this report the history of calorie restriction is briefly reviewed, and a mechanism of action is proposed that involves increased production of ACTH and decreased production of gonadotrophins. It is further proposed that these changes may come about in part from the restriction of the time during which feeding is permitted as well as from the restriction of food per se. There is renewed interest in calorie restriction due in part to the growing recognition that there are differences in the efficiency of utilization of various sources of energy, in particular that fat calories are utilized more efficiently and provide more usable energy than carbohydrate calories. New data are presented indicating that the apparent enhancement by dietary fat of mammary cancer in rats is really a manifestation of the caloric effect. Further, the effect is abolished by moderate calorie restriction of only 15-20%. The application of these findings to the prevention of cancer in humans is considered.