Modern, biologic root canal therapy should be performed with suitable irrigating solutions and intracanal medicaments. The goal of endodontic treatment is to free the treated tooth from infection and prevent reinfection as thoroughly as possible by means which do not put the organism at risk. In this review of the literature, an evidence-based concept for irrigation and medication of root canal systems is presented. Irrigants and medicaments are discussed with respect to their antimicrobial, tissue-dissolving and endotoxin-decontaminating capacity in relation to their systemic toxicity. Recent findings pertaining to interactions of root canal medicaments and irrigating solutions and their impact on a sound irrigating and medicating concept are discussed.