Research reveals that the opportunities for healthy choices in homes, neighborhoods, schools, and workplaces can have decisive impacts on health. This article reviews scientific evidence from promising interventions focused on the social determinants of health, and describes ways in which they can improve population health and reduce health disparities. We show that there is sufficient evidence to support policy interventions targeted at education and early childhood; urban planning and community development; housing; income enhancements and supplements; and employment. When available, cost-effectiveness evaluations show that these interventions lead to long-term societal savings; however, more routine attention to cost considerations is needed for these interventions. We also discuss challenges to implementation, including the need for long-term financing in order to scale-up effective interventions for implementation at the local, state, or national level. Although we know enough to act, questions remain about how to optimally scale-up these interventions and maximize their benefits for the most vulnerable populations.