Continuous renal replacement therapy (CRRT), which provides gradual, predictable clearance and fluid removal, is commonly used to manage acute kidney injury (AKI) and fluid overload in critically ill children. The Prospective Pediatric CRRT (ppCRRT) Registry, founded in 2001 and comprising 13 pediatric centers in the United States, represents the largest cohort of children receiving CRRT to date. Data from the ppCRRT has been used to describe pediatric CRRT demographics and epidemiology, improve technical aspects of CRRT provision for children, and identify novel or underappreciated risk factors affecting survival. Whereas the registry has successfully answered many questions, a number of questions remain unanswered and new ones have arisen. This article describes the ppCRRT Registry, including its major findings, the lessons learned, and the limitations inherent in its design. Additionally, using the registry as a framework, areas of future study are identified and potential methodologies examined.