The United States ranks in the lower tiers of OECD countries in life expectancy, and recent studies indicate that socioeconomic inequalities in health have been widening in the past decades. Over this period, many rigorous longitudinal studies have identified important social, behavioral, and environmental conditions that might reduce health disparities if we could design effective interventions and make specific policy changes to modify them. Often, however, neither our policy changes nor our interventions are as effective as we hoped they would be on the basis of findings from observational studies. Reviewed here are issues related to causal inference and potential explanations for the discrepancy between observational and experimental studies. We conclude that more attention needs to be devoted to (a) identifying the correct etiologic period within a life-course perspective and (b) understanding the dynamic interplay between interventions and the social, economic, and environmental contexts in which interventions are delivered. Expected final online publication date for the Annual Review of Public Health Volume 30 is March 17, 2009. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.