In the European Mediterranean basin, pasture-based sheep farming systems are mostly located in marginal/High Nature Value areas. These production systems are multifunctional, and their economic, environmental and social roles are equally important and recognised by policy makers and by society. However, the number of animals and holdings is decreasing, and there is great uncertainty regarding the reproducibility of these farming systems, which depends on many internal and external farm factors and their interactions. The aim of this paper was to perform a comprehensive assessment of sustainability in different sheep farming systems in north eastern Spain using the MESMIS framework. We followed a case-study approach to perform an in-depth investigation of 4 sheep meat and dairy farms with different intensities of reproduction management. Critical points of sustainability, including weaknesses and opportunities, were obtained using a participatory process with stakeholders (farmers and technical advisers) that resulted in the selection of 37 sustainability indicators that were classified according to the systemic attributes defined by MESMIS (productivity, stability, self-reliance, adaptability, equity) and according to the classical sustainability pillars (social, economic and environmental). Some underlying patterns could be observed when analysing sustainability pillars, attributes and indicators. A positive relationship between productivity and intensification level in meat farms was observed; however, economic sustainability was determined not only by on-farm but also by off-farm activities. The economic efficiency of farming (without considering subsidies) was mainly explained by the capture of added value in the dairy systems and the combination of high animal productivity as well as high forage and feed self-sufficiency in the meat systems. Social issues were also central to explaining sustainability at the farm level, including the prospects of generational turnover and the manner in which farmers perceive and rate their activity. A clear trade-off between economic and environmental indicators was observed, i.e., the higher the economic sustainability, the lower the environmental sustainability. Each farm scored differently for diverse attributes, pillars and individual indicators. The scores differed according to size, structure, resource availability and managerial skills, which implies that it would be difficult to apply a holistic sustainability analysis to farming systems instead of individual farms. A number of methodological questions arose during the evaluation process relative to the stakeholders perception of these indicators, their relevance and meaning, the reference values for comparison, or their validity to assess sustainability across spatial and temporal scales. These questions are discussed in the paper.