Comparative effectiveness research (CER) has the potential to transform the current health care delivery system by identifying the most effective medical and surgical treatments, diagnostic tests, disease prevention methods, and ways to deliver care for specific clinical conditions. To be successful, such research requires the identification, capture, aggregation, integration, and analysis of disparate data sources held by different institutions with diverse representations of the relevant clinical events. In an effort to address these diverse demands, there have been multiple new designs and implementations of informatics platforms that provide access to electronic clinical data and the governance infrastructure required for interinstitutional CER. The goal of this manuscript is to help investigators understand why these informatics platforms are required and to compare and contrast 6 large-scale, recently funded, CER-focused informatics platform development efforts. We utilized an 8-dimension, sociotechnical model of health information technology to help guide our work. We identified 6 generic steps that are necessary in any distributed, multi-institutional CER project: data identification, extraction, modeling, aggregation, analysis, and dissemination. We expect that over the next several years these projects will provide answers to many important, and heretofore unanswerable, clinical research questions.