In the face of budget cuts, ageing society as well as rising costs and complexity of treatments, health systems around the globe are nowadays confronted with the challenge of ensuring high quality care to citizens more efficiently and comprehensively. To meet this challenge, health related processes have to be appropriately supported by health information systems (HIS). Meaningful communication and cooperation of such HIS in the sense of semantic interoperability require the acknowledgment of health domain specific reference information models, service specifications, standardized terminologies, and reference architectures. For solving the problems, the traditional gap between informatics and software engineering, but also system engineering on the one hand and health informatics, medicine, public health and related disciplines on the other hand has to be bridged. In that context, a number of inconsistent standards and other sources of existing, health-related knowledge representation have to be managed.The main problem scientifically addressed in this dissertation is the lack of formal methods, methodologies, and appropriate processes to support the development (requirement analysis, design, implementation, evaluation, use, and maintenance) of semantically interoperable health information systems and components based on existing healthcare standards. As response to this problem, the thesis formulates and demonstrates a methodological framework to support the implementation of semantically interoperable health information systems based on an architecture-centered development process.