Biomedical interventions promise achievement of health-related Millennium Development Goals provided social-, capacity- and knowledge-based constraints to scaling up and reaching marginalized people at risk, are addressed, and balance between prevention and treatment is struck. We argue for a new approach: multi-stakeholder capacity building and learning for empowerment: MuSCLE. MuSCLE is used as a way to frame three systemic weaknesses in traditional health science and policy approaches: (1) a lack of engagement with people at risk to build a collective understanding of the contexts of health problems, including social drivers; (2) a lack of multi-criteria evaluation of alternative interventions; (3) a lack of attention paid to integrated capacity building. The MuSCLE framework responds in three ways: (1) participatory assessment of the ecological, socio-cultural, economic and political contexts of health, identifying priorities using risk and vulnerability science, and modeling drivers; (2) selection among intervention alternatives that makes ecological, socio-cultural, economic and political tradeoffs transparent; (3) integrated capacity building for sustainable and adaptive interventions. Literature and field lessons support the argument, and guidelines are set down. A MuSCLE approach argues for a transformation in health science and policy in order to achieve Millennium Development Goals for health.