In previous prevention studies, molecular targets were not intended. We then proposed the concept termed “molecular-targeting prevention” and applied it to cancer prevention. In most malignant tumors, tumor-suppressor genes, the retinoblastoma gene (RB) and/or the p53 gene are considered to be inactivated. We therefore hypothesized that RB and/or p53 might be good candidates for the molecular-targeting prevention of cancer. Interestingly, many cancer-preventive food factors were found to reactivate the lost functions of RB and/or p53 by a “gene-regulating chemoprevention” strategy. We next proposed the concept termed “combination-oriented molecular-targeting prevention”, in which only the preventive effects are synergistically enhanced. We then investigated the TNF-related apoptosis-inducing ligand (TRAIL)-death receptor 5 (DR5) pathway as a candidate of the target, and found that many cancer-preventive food factors could enhance the pathway resulting in the synergistic apoptosis of various cancer cells. We hope that these strategies will contribute to the prevention of cancer.