The goal of root canal treatment is the healing of the inflamed apical periodontium or the prevention of inflammation. Sufficient biocompatibility of materials used in the course of treatment is considered as a prime prerequisite for an undisturbed healing, in addition to other factors such as tight sealing of the root canal. Recently, new materials have been introduced – so-called bioactive materials – that are supposed to actively promote the healing process, for instance the regeneration of the periapical bony tissue. In this chapter, information on the composition, setting reaction and release of substances is provided as the basis for a detailed review of the mainly local toxicity and allergic reactions to root canal filling materials. Emphasis is placed on how biocompatibility determines the choice of dental material in each individual patient. In particular, new materials, e.g. resin-based composites, silicones or mineral trioxide aggregates used for root canal filling, are critically reviewed.