Investigation into the influence of energy restriction in cancer has gone through 3 distinct periods. After the initial observation by Moreschi in 1909, there was about a decade of active research in this area. Then interest waned, possibly because the field had gone as far as it could, considering the knowledge and methodology available at the time. Interest was rekindled in 1940 due, principally, to the work coming from the laboratories of Tannenbaum at the Michael Reese Hospital in Chicago and Baumann at the University of Wisconsin. Another decade of active research followed. In this period, we learned how to design experimental diets and interest was expressed in dietary constituents. By 1950, publications on this type of research had dwindled and the field lay virtually dormant for 30 years. Since the early 1980's, research on this topic has blossomed and we now know enough about physiology and molecular biology to probe the mechanisms underlying the phenomenon. Energy flux, as in exercise, also inhibits carcinogenesis. Energy restriction modulates oxidative DNA damage and enhances DNA repair. It is now apparent that energy restriction affects adrenal metabolism (as hypothesized by Boutwell in 1949), insulin metabolism, and various aspects of gene expression. Understanding the basic mechanisms should provide important insights into control of tumor proliferation.