Stakeholders in the clinical research enterprise are aligned around the need to make clinical research in general, and randomized controlled trials in particular, more meaningful and efficient. To that end, we have built distributed research networks (DRNs) for the Sentinel System, the National Institutes of Health (NIH) Collaboratory, and the National Patient-Centered Clinical Research Network (PCORnet). DRNs reuse electronic health record (EHR) and claims data for research. The design and use of health data DRNs is complicated by lack of uniformity in data collection, a fragmented healthcare system, and the imperative to protect research participants. We describe the key elements of successful DRNs, as well as methods, challenges, and solutions we have encountered in using DRNs to support different phases of randomized, multi-site, clinical research. This work supports "real-world" efforts to build a learning health system and will enable others to conduct randomized clinical trial research using a DRN.