BACKGROUND The health sciences are based upon information. Clinical information is usually stored and managed by physicians with precarious tools, such as spreadsheets. The biomedical domain is more complex than other domains that have adopted information and communication technologies as pervasive business tools. Moreover, medicine continuously changes its corpus of knowledge because of new discoveries and the rearrangements in the relationships among concepts. This scenario makes it especially difficult to offer good tools to answer the professional needs of researchers and constitutes a barrier that needs innovation to discover useful solutions. OBJECTIVE The objective was to design and implement a framework for the development of clinical data repositories, capable of facing the continuous change in the biomedicine domain and minimizing the technical knowledge required from final users. METHODS We combined knowledge management tools and methodologies with relational technology. We present an ontology-based approach that is flexible and efficient for dealing with complexity and change, integrated with a solid relational storage and a Web graphical user interface. RESULTS Onto Clinical Research Forms (OntoCRF) is a framework for the definition, modeling, and instantiation of data repositories. It does not need any database design or programming. All required information to define a new project is explicitly stated in ontologies. Moreover, the user interface is built automatically on the fly as Web pages, whereas data are stored in a generic repository. This allows for immediate deployment and population of the database as well as instant online availability of any modification. CONCLUSIONS OntoCRF is a complete framework to build data repositories with a solid relational storage. Driven by ontologies, OntoCRF is more flexible and efficient to deal with complexity and change than traditional systems and does not require very skilled technical people facilitating the engineering of clinical software systems.