Stress is one of the most powerful experiences to influence health and disease. Through epigenetic mechanisms, stress may generate a footprint that propagates to subsequent generations. Programming by prenatal stress or adverse experience in parents, grandparents, or earlier generations may thus be a critical determinant of lifetime health trajectories. Changes in regulation of microRNAs (miRNAs) by stress may enhance the vulnerability to certain pathogenic factors. This review explores the hypothesis that miRNAs represent stress‐responsive elements in epigenetic regulation that are potentially (...) heritable. Recent findings suggest that miRNAs are key players linking adverse early environments or ancestral stress with disease risk, thus they represent useful predictive disease biomarkers. Since miRNA signatures of disease are potentially heritable, big data management platforms will be vital to harness multi‐generational information and capture succinct yet potent biomarkers capable of directing preventative treatments. This feature would offer a unique window of opportunity to advance personalized medicine. (shrink)