Current approaches to environmental protection and development on land, along rivers and coastal zones, and in marine environments are struggling to effectively promote sustainability. This is partly due to limited understanding of how ecosystems are linked, and partly due to fragmented governance and management arrangements in the continuum from source to sea that hinders cooperation and strategic overview across connected systems. Meanwhile, the key flows that link ecosystems are being altered by climate change and by an intensification of human activities, which are also expanding offshore where management regimes are typically weak or non-existent. This paper presents a conceptual framework to guide the design of future initiatives aimed at supporting green and blue growth in source-to-sea systems. It includes a taxonomy of key flows, elements to guide analysis and planning and a common framework for elaborating a theory of change. Assembling a governance baseline and engaging stakeholders are critical elements in the approach. The conceptual framework builds on recent experiences of pro-sustainability action in source-to-sea systems around the world, and the paper applies the theory of change framework to selected case studies in order to develop further insights.