Abstract Background Agri-food is one of the most important sectors of the industry in Europe and potentially a major contributor to the global warming. Sustainability issues in this context pose a huge challenge for several reasons: the variety of considered scales, the number of disciplines involved, the uncertainties, the out-of-equilibrium states, the complex quantitative and qualitative factors, the normative issues and the availability of data. Although important insight and breakthroughs have been attained in different scientific domains, an overarching and integrated analysis of these complex problems have yet to be realized. Scope and Approach This context creates huge opportunities for research in interaction with mathematical programming, integrative models and decision-support tools. The paper propose a computational viewpoint including questions of holistic approach, multiscale reconstruction and optimization. Some directions are discussed. Key Findings and Conclusions Several research questions based on a mathematical programming framework are emerging: how can such a framework manage uncertainty, cope with complex qualitative and quantitative information essential for social and environmental considerations, encompass diverse scales in space and time, cope with a multivariable dynamic environment and with scarcity of data. Moreover, how can it deal with different perspectives, types of models, research goals and data produced by conceptually disjoint scientific disciplines, ranging from physics and physiology to sociology and ethics? Building models is essential, but highly difficult; it will need a strong iterative interaction combining computational intensive methods, formal reasoning and the experts of the different fields. Some future research directions are proposed, involving all those dimensions: mathematical resilience, human-machine interactive learning and optimization techniques.