Regenerative endodontic procedures (REPs) have been shown to promote the resolution of signs and symptoms of disease and increase survival compared with traditional treatment procedures. However, there is still variable predictability of continued root development and evidence that the tissues formed do not recapitulate the native pulp-dentin complex. There is growing evidence that the apical papilla is capable of surviving prolonged endodontic infection and apical periodontitis and that it represents a rich source of undifferentiated mesenchymal stem cells in REPs. The survival and proper differentiation of stem cells transferred into infected root canals are fraught with challenges. Residual antigens, such as lipopolysaccharides, have been shown to be present in dentin even after adequate chemomechanical debridement. These antigens have a profound effect on stem cell fate by modulating their proliferative capacity and postdifferentiation phenotype. Thus, root canals must be detoxified in addition to disinfection. There is a strong need for translational studies that incorporate all aspects of tissue engineering in endodontics in models that include an existing infection to promote further advancement of the field. This is particularly important to make REPs more predictable when treating immature teeth in young patients. Importantly, regenerative procedures could eventually promote tooth longevity in our aging population. Lessons learned from translational studies that best mimic the clinical challenges could be evaluated in pragmatic clinical trials to determine the effectiveness of these procedures to promote desirable patient-centered outcomes.