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According to the American Dental Association Survey of Dental Services Rendered (published in 2007), 15 million root canal treatment procedures are performed annually. Endodontic therapy relies mainly on biomechanical preparation, chemical irrigation and intracanal medicaments which play an important role in eliminating bacteria in the root canal. Furthermore, adequate obturation is essential to confine any residual bacteria within the root canal and deprive them of nutrients. However, numerous studies have shown that complete elimination of bacteria is not achieved due to the complex anatomy of the root canal system. There are several conventional antibiotic materials available in the market for endodontic use. However, the majority of these antibiotics and antiseptics provide short-term antibacterial effects, and they impose a risk of developing antibacterial resistance. The root canal is a dynamic environment, and antibacterial and antibiofilm materials with long-term effects and nonspecific mechanisms of action are highly desirable in such environments. In addition, the application of acidic solutions to the root canal wall can alter the dentin structure, resulting in a weaker and more brittle dentin. Root canal sealers with bioactive properties come in direct contact with the dentin wall and can play a positive role in bacterial elimination and strengthening of the root structure. The new generation of nanostructured, bioactive, antibacterial and remineralizing additives into polymeric resin-based root canal sealers are discussed in this review. The effects of these novel bioactive additives on the physical and sealing properties, as well as their biocompatibility, are all important factors that are presented in this article.