There is overwhelming evidence that social factors have profound influences on health. Children are particularly sensitive to social determinants, especially in the early years. Life course models view health as a developmental process, the product of multiple gene and environment interactions. Adverse early social exposures become programmed into biological systems, setting off chains of risk that can result in chronic illness in mid-life and beyond. Positive health-promoting influences can set in motion a more virtuous and health-affirming cycle, leading to more optimal health trajectories. Mounting an effective response to social determinants will involve both direct social policy initiatives designed to eliminate poverty and inequality, and indirect approaches focused on disrupting pathways between social risks and poor health outcomes. To be effective, these indirect strategies will require nothing short of a transformation of existing child health systems. Parents and professionals must work together from the ground up, raising public awareness about social determinants of health and implementing cross-sector place-based initiatives designed to promote positive health in childhood.