There is considerable scientific and policy interest in reducing socioeconomic and racial/ethnic disparities in healthcare and health status. Currently, much of the policy focus around reducing health disparities has been geared toward improving access, coverage, quality, and the intensity of healthcare. However, health is more a function of lifestyles linked to living and working conditions than of healthcare. Accordingly, effective efforts to improve health and reduce gaps in health need to pay greater attention to addressing the social determinants of health within and outside of the healthcare system. This article highlights research evidence documenting that tackling the social determinants of health can lead to reductions in health disparities. It focuses both on interventions within the healthcare system that address some of the social determinants of health and on interventions in upstream factors such as housing, neighborhood conditions, and increased socioeconomic status that can lead to improvements in health. The studies reviewed highlight the importance of systematic evaluation of social and economic policies that might have health consequences and the need for policy makers, healthcare providers, and leaders across multiple sectors of society to apply currently available knowledge to improve the underlying conditions that impact the health of populations.