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The Electronic Data Methods (EDM) Forum brings together perspectives from the Prospective Outcome Systems using Patient-specific Electronic data to Compare Tests and therapies (PROSPECT) studies, the Scalable Distributed Research Networks, and the Enhanced Registries projects. This paper discusses challenges faced by the research teams as part of their efforts to develop electronic clinical data (ECD) infrastructure to support comparative effectiveness research (CER). The findings reflect a set of opportunities for transdisciplinary learning, and will ideally enhance the transparency and generalizability of CER using ECD.Findings are based on 6 exploratory site visits conducted under naturalistic inquiry in the spring of 2011. Themes, challenges, and innovations were identified in the visit summaries through coding, keyword searches, and review for complex concepts.The identified overarching challenges and emerging opportunities include: the substantial level of effort to establish and sustain data sharing partnerships; the importance of understanding the strengths and limitations of clinical informatics tools, platforms, and models that have emerged to enable research with ECD; the need for rigorous methods to assess data validity, quality, and context for multisite studies; and, emerging opportunities to achieve meaningful patient and consumer engagement and work collaboratively with multidisciplinary teams.The new infrastructure must evolve to serve a diverse set of potential users and must scale to address a range of CER or patient-centered outcomes research (PCOR) questions. To achieve this aim—to improve the quality, transparency, and reproducibility of CER and PCOR-a high level of collaboration and support is necessary to foster partnership and best practices as part of the EDM Forum.