In the United States, awareness is increasing that medical care alone cannot adequately improve health overall or reduce health disparities without also addressing where and how people live. A critical mass of relevant knowledge has accumulated, documenting associations, exploring pathways and biological mechanisms, and providing a previously unavailable scientific foundation for appreciating the role of social factors in health. We review current knowledge about health effects of social (including economic) factors, knowledge gaps, and research priorities, focusing on upstream social determinants-including economic resources, education, and racial discrimination-that fundamentally shape the downstream determinants, such as behaviors, targeted by most interventions. Research priorities include measuring social factors better, monitoring social factors and health relative to policies, examining health effects of social factors across lifetimes and generations, incrementally elucidating pathways through knowledge linkage, testing multidimensional interventions, and addressing political will as a key barrier to translating knowledge into action.