The evolution of chemoprevention research continues in exciting new directions. Large chemoprevention trials in unselected patients have often been negative, but this trend promises to be reversed by more-focused and novel trial designs emphasizing the identification of molecular targets and predictive biomarkers. Phase 0 designs, blood and tissue-based biomarkers, and surrogate endpoints are examples of important features of new prevention-trial design. Breakthroughs in the identification of novel mechanisms of carcinogenesis have contributed to a better understanding of key signaling pathways in cancer development. There has been substantial progress in elucidating molecular targets of promising synthetic and natural agents such as epigallocatechin gallate, indole-3-carbinol, myo-inositol, and deguelin, raising great optimism that biomarkers predicting efficacy, such as those associated with metformin effects, will be identified. This review will highlight several promising natural agents and how early clinical development may elucidate their role in personalized cancer chemoprevention.