Advances in biology are providing deeper insights into how early experiences are built into the body with lasting effects on learning, behavior, and health. Numerous evaluations of interventions for young children facing adversity have demonstrated multiple, positive effects but they have been highly variable and difficult to sustain or scale. New research on plasticity and critical periods in development, increasing understanding of how gene-environment interaction affects variation in stress susceptibility and resilience, and the emerging availability of measures of toxic stress effects that are sensitive to intervention provide much-needed fuel for science-informed innovation in the early childhood arena. This growing knowledge base suggests 4 shifts in thinking about policy and practice: (1) early experiences affect lifelong health, not just learning; (2) healthy brain development requires protection from toxic stress, not just enrichment; (3) achieving breakthrough outcomes for young children facing adversity requires supporting the adults who care for them to transform their own lives; and (4) more effective interventions are needed in the prenatal period and first 3 years after birth for the most disadvantaged children and families. The time has come to leverage 21st-century science to catalyze the design, testing, and scaling of more powerful approaches for reducing lifelong disease by mitigating the effects of early adversity.