Local wound debridement in the diseased pulp space is the main step in root canal treatment to prevent the tooth from being a source of infection. In this review article, the specifics of the pulpal microenvironment and the resulting requirements for irrigating solutions are spelled out. Sodium hypochlorite solutions are recommended as the main irrigants. This is because of their broad antimicrobial spectrum as well as their unique capacity to dissolve necrotic tissue remnants. Chemical and toxicological concerns related to their use are discussed, including different approaches to enhance local efficacy without increasing the caustic potential. In addition, chelating solutions are recommended as adjunct irrigants to prevent the formation of a smear layer and/or remove it before filling the root canal system. Based on the actions and interactions of currently available solutions, a clinical irrigating regimen is proposed. Furthermore, some technical aspects of irrigating the root canal system are discussed, and recent trends are critically inspected.