This dissertation tackles the problematic of Enterprise Interoperability in the current globally connected world. The evolution of the Information and Communication Technologies has endorsed the establishment of fast, secure and robust data exchanges, promoting the development of networked solutions. This allowed the specialisation of enterprises (particularly SMEs) and favoured the development of complex and heterogeneous provider systems. Enterprises are abandoning their self-centrism and working together on the development of more complete solutions. Entire business solutions are built integrating several enterprises (e.g., in supply chains, enterprise nesting) towards a common objective. Additionally, technologies, platforms, trends, standards and regulations keep evolving and demanding enterprises compliance. This evolution needs to be continuous, and is naturally followed by a constant update of each networked enterprise’s interfaces, assets, methods and processes. This unstable environment of perpetual change is causing major concerns in both SMEs and customers as the current interoperability grounds are frail, easily leading to periods of downtime, where business is not possible. The pressure to restore interoperability rapidly often leads to patching and to the adoption of immature solutions, contributing to deteriorate even more the interoperable environment. This dissertation proposes the adoption of NEGOSEIO, a framework that tackles interoperability issues by developing strong model-based knowledge assets and promoting continuous improvement and adaptation for increasing the sustainability of interoperability on enterprise systems. It presents the research motivations and the developed framework’s main blocks, which include model-based knowledge management, collaboration service-oriented architectures implemented over a cloud-based solution, and focusing particularly on its negotiation core mechanism to handle inconsistencies and solutions for the detected interoperability problems. It concludes by validating the research and the proposed framework, presenting its application in a real business case of aerospace mission design on the European Space Agency (ESA).