Recent systematic reviews have substantiated the fact that current testing methods to assess the inflammatory state of the pulp and the periapical tissues are of limited value. Consequently, it may be time to search for alternative routes in endodontic diagnostics. Molecular assessment methods could be the future. However, in the field of endodontics, the research in that direction is only about to evolve. Because pulpal and periradicular diseases are related to opportunistic infections, diagnostics can either target microorganisms or the host reaction. This communication discusses clinical situations in which a molecular assessment of infection or host reaction could be of interest. The methods, collection sites, current state of research, and unresolved problems are evaluated.