The Distributed Ambulatory Research in Therapeutics Network (DARTNet) is a federated network of electronic health data from 8 organizations representing more than 500 clinicians and more than 400 000 patients. DARTNet was designed to increase knowledge of the comparative effectiveness of prescription medications and medical devices. Traditional observational comparative effectiveness research is conducted using large data sets, such as claims databases. Such databases do not provide important clinical information that is critical to understanding comparative effectiveness. By linking electronic health records, laboratory and imaging data, and administrative data from diverse and geographically disparate patients, DARTNet provides important new insight into the comparative effectiveness of oral diabetes medications, and it is ready for expansion to further enable effectiveness research.