Today an unprecedented opportunity exists to improve health in some of the world’s poorest and most vulnerable communities by tackling the root causes of disease and health inequalities. The most powerful of these causes are the social conditions in which people live and work, referred to as the social determinants of health (SDH). The Millennium Development Goals (MDGs) shape the current global development agenda. The MDGs recognize the interdependence of health and social conditions and present an opportunity to promote health policies that tackle the social roots of unfair and avoidable human suffering. The Commission on Social Determinants of Health (CSDH) is poised for leadership in this process. To reach its objectives, however, the CSDH must learn from the history of previous attempts to spur action on SDH. This paper pursues three questions: (1) Why didn’t previous efforts to promote health policies on social determinants succeed? (2) Why do we think the CSDH can do better? (3) What can the Commission learn from previous experiences – negative and positive – that can increase its chances for success?