Dietary approaches to cancer chemoprevention increasingly have focused on single nutrients or phytochemicals to stimulate one or another enzymatic metabolizing system. These procedures, which aim to boost carcinogen detoxification or inhibit carcinogen bioactivation, fail to take into account the multiple and paradoxical biological outcomes of enzyme modulators that make their effects unpredictable. Here, we critically examine the scientific and medical evidence for the idea that the physiological roles of specific enzymes may be manipulated by regular, long-term administration of isolated nutrients and other chemicals derived from food plants. Instead, we argue that consumption of healthful diets is most likely to reduce mutagenesis and cancer risk, and that research efforts and dietary recommendations should be redirected away from single nutrients to emphasize the improvement of dietary patterns as a principal strategy for public health policy.