Register-based research offers a good opportunity to generate knowledge on questions from the clinical practice. Methodologically high-quality register studies can complement clinical studies, especially for questions that cannot be answered with randomized controlled trials (RCT). The ad hoc committee on healthcare data of the German Network for Health Services Research (DNVF) has set methodological guidelines for register-based studies with a manual for methods and the use of healthcare data. The methodological advantages of both approaches can be integrated through RCTs embedded in registers. In Germany there is a diverse register landscape as shown by the register report commissioned by the Federal Ministry of Health, which, however, show a varying degree of internationally recognized quality criteria. The relevance of register-based studies for the clinical practice (e. g. guideline development) is shown in the examples of applications cited in the article. Although a lot has already been done here in Germany with existing register data, sustainable coordination and promotion of the research infrastructure and research culture, especially in international comparison are necessary.