Background: Apical periodontitis (AP) is considered a biofilm-induced disease. Treatment of AP relies on biofilm disinfection. The finite capacity of endodontic instruments to eliminate biofilms from the intricate root canal system has established irrigation as the principal determinant of disinfection. From an inferential point of view, enhancing the irrigation efficacy should lead to improved control of the root canal biofilm infection, which, in turn, should be reflected on increased treatment success. Within this context, the level of disinfection achieved by irrigation is considered as a valid surrogate endpoint predicting treatment success. Despite the intuitive positive association between improvement of surrogate endpoints and increased treatment outcome success, clinical investigations have failed to corroborate it. In clinical endodontic research, it is inherently difficult to standardize and isolate parameters of interest and mechanistically explore the action of irrigants. These constraints prompt researchers to develop translational laboratory models to increase generalizability to the clinical setting. In endodontic irrigation research, converting fragmented knowledge derived from basic research into translational laboratory models is a demanding task. It requires appreciation of disease etiology and root canal configuration, creative engineering, laborious optimization steps, and multimodal assessment tools. These research facets are construed as development of appropriate biofilm models, realistic root canal models, and selection of a broad range of evaluation tools for appreciating the antibiofilm capacity of irrigants. Aim: to present methodological aspects of research on endodontic irrigation-driven biofilm disinfection and challenges that need to be considered for the effective transition from basic to translational research.