Deep space missions are characterized by severely constrained communication links. To meet the needs of future missions and increase their scientific return, future space systems will require an increased level of autonomy on-board. In this work, we propose a comprehensive approach to on-board autonomy relying on model-based reasoning, and encompassing many important reasoning capabilities such as plan generation, validation, execution and monitoring, FDIR, and run-time diagnosis. The controlled platform is represented symbolically, and the reasoning capabilities are seen as symbolic manipulation of such formal model. We have developed a prototype of our framework, implemented within an on-board Autonomous Reasoning Engine. We have evaluated our approach on two case-studies inspired by real-world, ongoing projects, and characterized it in terms of reliability, availability and performance.