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Enamel matrix derivative (EMD) is a protein extract used for the treatment of periodontal defects and soft tissue recession. Its use in endodontics has been a subject of exploration, especially in regenerative procedures. The aim of this review was to evaluate the current literature available on the application of EMD in the field of endodontics.An initial literature search of databases using different combinations of the search terms yielded 1089 articles. From the 29 qualified studies, there were 17 animal studies and 12 human case series and clinical trials.The evidence for the application of EMD as a direct pulp capping agent was relatively dichotomous. In determining the possible effect of EMD on pulpotomy procedures, only 1 animal study qualified under the criteria set forth previously. When comparing EMD against calcium hydroxide (Ca[OH]2), Portland cement, and mineral trioxide aggregate (MTA), Ca(OH)2 induced more histologic hard tissue formation, whereas MTA performed best clinically and radiographically. The scientific literature available is inconclusive on the effectiveness of EMD in preventing root resorption. In regeneration, EMD treatment induced mainly the formation of a cementumlike tissue at the apical region of the root's external surface and showed an ingrowth of newly formed hard tissues into the root canal space.The results of EMD application in endodontic treatments are highly variable, warranting additional research, specifically in the subjects of replantation and regeneration/revascularization.Enamel matrix derivative (EMD) is known to promote new bone, cementum, periodontal ligament formation, and regeneration.Evidence in the literature suggests that EMD can be applied in direct pulp capping and pulpotomy.EMD may have a potential in the treatment of traumatized and immature teeth.