Dentin is the largest substrate available whenever restorative procedures are implemented on the exposed crown or root of teeth. In endodontics, restorative/obturating procedures are practically restricted to dentin. It is well recognized that the incidence of fracture in endodontically treated teeth is intrinsically related to the amount of remaining dentin. Ideally, it is expected that a gap‐free, solid interface can be formed between the restorative/obturating materials and root dentin, providing an impervious seal and, simultaneously, fracture resistance to root‐filled teeth. Over the past years, a number of new obturating biomaterials have been launched in the market, bringing to endodontists the expectation of achieving consistent sealing/reinforcing of the root canal system. However, the successful sealing of root dentin remains one of the greatest challenges in restorative dentistry. This article will focus on reviewing some factors that affect the formation and integrity of dentin–biomaterial interfaces from the perspective of the dentin substrate. Because other articles in preceding issues of Endodontic Topics have already covered dentin structure and composition, the objective here is not to review these aspects. Specific attention is given, however, to depicting how chemical treatments affect existing root filling/restorative mechanisms and how some microbial and host‐related aspects can compromise the interaction of dentin with new biomaterials.