The success of endodontic treatment depends on the eradication of microbes (if present) from the root-canal system and prevention of reinfection. The root canal is shaped with hand and rotary instruments under constant irrigation to remove the inflamed and necrotic tissue, microbes/biofilms, and other debris from the root-canal space. The main goal of instrumentation is to facilitate effective irrigation, disinfection, and filling. Several studies using advanced techniques such as microcomputed tomography (CT) scanning have demonstrated that proportionally large areas of the main root-canal wall remain untouched by the instruments,1 emphasizing the impor- tance of chemical means of cleaning and disinfecting all areas of the root canal (Figs. 1 and 2). There is no single irrigating solution that alone sufficiently covers all of the functions required from an irrigant. Optimal irrigation is based on the combined use of 2 or several irrigating solutions, in a specific sequence, to predictably obtain the goals of safe and effective irrigation. Irrigants have traditionally been delivered into the root-canal space using syringes and metal needles of different size and tip design. Clinical experience and research have shown, however, that this classic approach typically results in ineffective irrigation, particularly in peripheral areas such as anasto- moses between canals, fins, and the most apical part of the main root canal. There- fore, many of the compounds used for irrigation have been chemically modified and several mechanical devices have been developed to improve the penetration and effectiveness of irrigation. This article summarizes the chemistry, biology, and proce- dures for safe and efficient irrigation and provides cutting-edge information on the most recent developments.