Conducting high-quality, generalizable clinical informatics research has never been more important or difficult. The increased importance stems from the astronomic rate of adoption of electronic health records (EHRs) due in large part to the American Recovery and Reinvestment Act of 2009 (ARRA). The increased difficulty is the result of many of the leading academic medical centers, where much of the ground-breaking clinical informatics research was done over the last 40 years, discontinuing their internal EHR development and moving to commercially-available EHR systems. The Clinical Informatics Research Collaborative (CIRCLE) attempts to overcome these challenges. CIRCLE is a network of applied academic clinical informaticians committed to improving our understanding of issues involved in the design, development, implementation, use and evaluation of all aspects of health information technology with a particular emphasis on EHRs.