The Millennium Development Goals (MDGs) galvanized attention, resources and accountability on a small number of health concerns of low- and middle-income countries with unprecedented results. The international community is presently developing a set of Sustainable Development Goals as the successor framework to the MDGs. This review examines the evidence base for the current health-related proposals in relation to disease burden and the technical and political feasibility of interventions to achieve the targets. In contrast to the MDGs, the proposed health agenda aspires to be universally applicable to all countries and is appropriately broad in encompassing both communicable and non-communicable diseases as well as emerging burdens from, among other things, road traffic accidents and pollution.We argue that success in realizing the agenda requires a paradigm shift in the way we address global health to surmount five challenges: 1) ensuring leadership for intersectoral coherence and coordination on the structural (including social, economic, political and legal) drivers of health; 2) shifting the focus from treatment to prevention through locally-led, politically-smart approaches to a far broader agenda; 3) identifying effective means to tackle the commercial determinants of ill-health; 4) further integrating rights-based approaches; and 5) enhancing civic engagement and ensuring accountability. We are concerned that neither the international community nor the global health community truly appreciates the extent of the shift required to implement this health agenda which is a critical determinant of sustainable development.