Over the past two decades, the global health agenda has increasingly embraced the concept of sustainable development in pursuit of solutions at the “systems” level. A central challenge is that the relevant social, economic and biophysical systems that influence human health and well-being operate at difference spatial and temporal scales and scopes of problem solving. Here, we explore three interconnected self-reinforcing systems of central importance to planetary health: the ecology of poverty, the ecology of disease, and systems of health care delivery. We frame these issues to inform how practical interventions can be implemented and studied to create practical systems-level change at the ground level and establish methods for evaluating that change and produce transferable knowledge for scaling or replication.