The world is continuously transforming to supply growing cities and urbanization processes are still driving important changes in our current food systems. Future sustainability constraints are emphasizing that Food Supply and Distribution Systems (FSDS) are deeply embedded in city-region systems with specific technical and socio-ecological characteristics. This paper aims to provide a systemic understanding on FSDS focusing the integration of urban and rural structures considering the system biophysical boundaries and societal targets. A qualitative framework model, based on the Food and Agriculture Organization of the United Nations (FAO)’s FSDS literature, has been developed by using Systems Thinking (ST) and System Dynamics (SD) approaches. The model analysis suggested that to increase sustainability and resilience of food systems large emphasis has to be maintained on: (i) estimation of local territorial carrying capacities; (ii) land use planning to enhance connections among rural supplies and city needs; (iii) city policies, to regulate emergent market size and local scale of production; (iv) technological efficiency at farm, distribution and market levels; (v) urban, peri-urban and rural functional linkages that considers social metabolic balances; (vi) rural development as a core point for building sustainable food systems and counteracting the urbanization growth. These key areas are relevant to test new paths of cities-regions reconfiguration towards the transition to resilient agri-food systems.