The success of endodontic treatment depends on the eradication of microbes 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. 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. 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 procedures for safe and efficient irrigation and provides cutting-edge information on the most recent developments.