Background: It is well recognized that disinfection of the complex root canal system at the apical root canal remains the most critical therapeutic measure to treat apical periodontitis. Materials and Methods: Observational and experimental data in relation to the anatomy of the apical root canal in different tooth types and the cross sectional diameters of the apical part of the most commonly used hand and rotary files are critically reviewed. Results: The present data analysis confirm that the challenging issue of antibacterial efficacy of modern preparation protocols in non-surgical endodontics requires more attention to apical root canal irrigation as a balance between safety and effectiveness. Ex vivo investigations clearly indicate that a specific design of the chemo-mechanical preparation is needed at the onset of RCT, more particularly in infected teeth. Design should be based on specific anatomical parameters, and must determine the appropriate size and taper of preparation as pre-requirements for effective and safe apical irrigation. Conclusions: The optimal irrigation protocols might be designed on the basis of technical specifications of the preparations procedures, such as the penetration depth, the type of the needle, the required time for continuous irrigant flow, the concentration of NaOCl, and the activation parameters.