Objectives: To address the problem of alignment of health information systems to healthcare processes, which is a major challenge in healthcare organizations; to present a layered approach for system evolution and adaptation based on an application framework and rapid application development; to accomplish a demand-driven system evolution by embedding the software engineering process in business process optimization projects and by closely involving end users to improve their own work practices. Methods: We have used a holistic health information system as a core application framework. System functionality is incrementally improved using an integrated “generator tool” for rapid application development. We have developed an iterative and participatory software engineering process, adapted to the conditions of the generator tool. The documentation techniques provided by the Unified Modeling Language (UML) were modified to achieve a straight forward documentation covering the whole development cycle from the business process model to generator-based computer applications. Results and conclusion: The layered approach for system evolution did provide an environment in which a flexible and participatory software development process could be established. Today, generator-based applications are used in all clinical departments of our 1200-bed University Hospital. We expect that tools for rapid application development will be further improved and will play an increasingly important role to establish responsive IT-infrastructures where the application developer can concentrate on business process alignment instead of coding and debugging.