Effectively reducing cumulative impacts on marine ecosystems requires co-evolution between science, policy and practice. Here, long-term social–ecological changes in the Baltic Sea are described, illustrating how the process of making the ecosystem approach operational in a large marine ecosystem can be stimulated. The existing multi-level governance institutions are specifically set up for dealing with individual sectors, but do not adequately support an operational application of the ecosystem approach. The review of ecosystem services in relation to regime shifts and resilience of the Baltic Sea sub-basins, and their driving forces, points to a number of challenges. There is however a movement towards a new governance regime. Bottom-up pilot initiatives can lead to a diffusion of innovation within the existing governance framework. Top-down, enabling EU legislation, can help stimulating innovations and re-organizing governance structures at drainage basin level to the Baltic Sea catchment as a whole. Experimentation and innovation at local to the regional levels is critical for a transition to ecosystem-based management. Establishing science-based learning platforms at sub-basin scales could facilitate this process.