A special issue on ethical and regulatory issues in pragmatic clinical trials has been published in the journal Clinical Trials. The effort was sponsored by the NIH Collaboratory, with additional support from the Patient-Centered Outcomes Research Institute (PCORI). As NIH Collaboratory pragmatic clinical trials were implemented, it became clear that ethical and regulatory complexities were some of the biggest challenges in conducting pragmatic clinical research. The NIH Collaboratory engaged groups of stakeholders, including researchers, patient advocates, bioethicists, and regulatory experts, to address a set of 11 ethical and regulatory issues. Each article in the special issue describes a particular ethical or regulatory challenge faced by pragmatic clinical trials and offers recommendations for how to protect the rights and welfare of research participants while enabling large-scale research that delivers critically needed evidence to healthcare decision-makers. The topics include alteration of informed consent, privacy, gatekeepers, vulnerable populations, and defining minimal risk research. An introduction was written by Robert M. Califf, MD, and Jeremy Sugarman, MD, MPH, who also served as editors of the issue.