Background and objectives: Countries of the Mediterranean region are undergoing different stages of nutritional transition affecting the health of inhabitants, while facing massive alteration of the environment (climate change, water scarcity, soil erosion, biodiversity loss and urbanization). The increasing demand of water in agriculture, the capacities to maintain local food production and the growing dependence on food imports are interconnected challenges to ensure food security and good nutrition in the Mediterranean region. The objective is to present the conceptual framework and methodologies developed by the MEDINA-Study Group for rethinking food systems to sustain consumption and production. Methods: Based on its multidisciplinary expertise in nutrition, food science, agronomy and economy, the MEDINA-Study Group identified the relevant parameters for including in a conceptual framework that was developed for research activities in South of France and Tunisia, two contrasted areas in regards to the Diet-Agriculture-Environment Nexus. Results: The conceptual framework consists of an array of elements of the food systems (from consumption to production) and scales (individual, household and national levels). We prioritized the following parameters: adherence to the Mediterranean diet pyramid and nutrient recommendations, nutritional value of foods and local recipes, nutritional potential of local agroecosystems, women?s empowerment in agriculture, multiple environmental indicators of the food systems, and food trade and dependence on food imports. The proposed methodologies consist in: (1) modeling at different scales the dietary changes to optimize food consumption-production without increasing environmental impact, (2) translating the identified changes into action proposals, (3) testing the acceptability and feasibility by multi-stakeholders, and (4) co-building guidelines to orientate sustainable food choices and production. Conclusions: To ensure sustainable food systems in the Mediterranean region, the MEDINA-Study Group identified other perspectives to implement the initially-build framework, such as the nutrient bioavailability, the exposure to contaminants and active substances used in agriculture, and social indicators to contribute designing ambitious agricultural, food and health policies and prioritizing actions. Acknowledgement: Medina-Study is funded by the French Research Agency (ANR-12-TMED-0004).