Managing trade-offs for ‘do no harm’ outcomes is central to achieving the Sustainable Development Goals. To bridge this development paradigm with still prominent development paradigms, an agri-food systems perspective provides a lens to explore the trade-offs in value chain interventions. Analyses of pro-poor value chains, nutrition-sensitive value chains, and greening of value chains reveal numerous problematic assumptions and a limited evidence base that supports these. Looking at these value chains from an agri-food system perspective allows us to unearth a degree of conflicting logics and targets requiring societal negotiation about goals and their hierarchy to speed up the achievement of the Sustainable Development Goals. Steps are outlined to embed a ‘do no harm’ principle in intervention design and evaluation.