This Perspective argues that rising early-onset cancers reflect not just new risks but fundamental limits in how cancer causes are currently studied. Existing epidemiologic tools—largely built around midlife exposures and static measurements—fail to capture the complex, life-course accumulation of environmental, behavioral, and biological factors that shape cancer risk. To address this gap, the authors propose integrating epidemiology with mechanistic biology and advancing three frameworks to better identify causes, predict risk, and estimate preventability across the life span.