Concerted efforts are underway to improve healthcare decision-making through patient-centered outcomes research. These efforts are supported by the Patient-Centered Outcomes Research Trust Fund, which was established within the Patient Protection and Affordable Care Act. This article focuses on describing national data infrastructure efforts that support patient-centered outcomes research. A national data infrastructure has the potential to decrease research costs and improve research throughput. We describe early and current efforts that demonstrated this potential, how the national effort is utilizing the lessons learned from these predecessor efforts and remaining challenges.