summary: Prevention and early detection is critical for reducing the population cancer burden. Two approaches have been used: Population approaches change social norms (e.g., smoking bans) or impose incentives (e.g., cigarette taxes); high-risk strategies intervene upon individuals with elevated cancer risk (e.g., smoking cessation). Knowledge about carcinogenesis mechanisms, extreme exposures, and inherited susceptibility provides opportunities to develop precision prevention and early-detection (PPED) strategies. PPED aims to understand the basis of risk, identify groups that optimally benefit from interventions, characterize heterogeneity in intervention responses, optimize intervention timing, and minimize toxicities. We propose a framework around which PPED strategies can be developed. Currently available cancer prevention and early-detection approaches have the potential to reduce a large proportion of the cancer burden in the population. However, even if fully implemented, existing methods cannot fully eliminate the cancer burden. New PPED approaches that exploit the growing knowledge of molecular and biological cancer mechanisms should be developed and implemented.