Achieving biocompatibility in a material requires an interdisciplinary approach that involves a sound knowledge of materials science, bioengineering, and biotechnology. The host microbial-material response is also critical. Endodontic treatment is a delicate procedure that must be planned and executed properly. Despite major advances in endodontic therapy in recent decades, clinicians are confronted with a complex root canal anatomy and a wide selection of endodontic filling materials that, in turn, may not be well tolerated by the periapical tissues and may evoke an immune reaction. This article discusses published reports of various bioactive materials that are used in endodontic therapy, including calcium hydroxide, mineral trioxide aggregate, a bioactive dentin substrate, calcium phosphate ceramics, and calcium phosphate cements.