Pragmatic clinical trials (PCTs) test clinical interventions (eg, treatments, diagnostic tests, delivery strategies) that are widely used in practice and for which there is often clinical equipoise. Similar to traditional explanatory trials of novel therapeutics, PCTs use randomization to decrease selection bias. In contrast, PCTs rely on extant data sources (eg, electronic medical records [EMRs]) and test interventions that can be implemented with minimal research infrastructures. Thus, PCTs have drawn interest as vehicles for decreasing the cost of clinical research and for creating learning health systems, which, as articulated by the Institute of Medicine, seek to generate new knowledge as an integral by-product of the delivery experience. However, realizing this vision for PCTs will require innovative approaches for engaging clinicians, improving the efficiency of subject recruitment, improving the reliability of EMR data, and new paradigms for the regulatory review of low-risk trials to decrease unncessary hurdles to practice-based knowledge generation.