The presence of micro-organisms within the root canal system is the critical aetiological factor in peri-radicular periodontitis. During root canal treatment (RCT) it is imperative that this infection and other organic debris are removed from the root canal system. This is challenging because complex tooth anatomy, the presence of a biofilm and the smear layer complicate the process. There are a number of irrigant chemicals and adjunctive systems available in contemporary endodontic practice that are used to disinfect the root canal system during root canal preparation. This article reviews the available evidence concerning these disinfection methods and concludes by presenting a clinical protocol supported by the literature. CPD/Clinical Relevance: A clinical protocol, supported by the literature, is presented for effective decontamination of the root canal system during root canal therapy.