The ultimate goal of our public health system is to reduce the incidence of disability and premature death. Evidence suggests that, by this standard, the USA falls behind most other developed countries largely as a function of disparities in health outcomes among significant portions of the US population. We present a framework for addressing these disparities that attributes them, not simply to differences in the behavioral and physical risk factors, but to social, environmental, and structural inequities such as poverty, discrimination, toxic physical setting, and the marketing of harmful products. These inequities result from de facto and instituted public policies. An analysis of the NIH research portfolio indicates a relative lack of investment in experimental evaluations of preventive interventions—especially studies targeting disadvantaged populations. Moreover, experimental research on reducing social inequities is almost entirely lacking. A line of research focusing on the drivers of inequities and their dissolution must include experimental evaluation of strategies for getting policies adopted that will reduce inequities. In conclusion, a summary is provided of the types of research that are needed and the challenges involved in conducting the experimental research that is essential for reducing inequities and disparities and, in turn, prolonging life.