Apical periodontitis, an inflammation of the periapical tissue most commonly occurring as a result of persistent bacterial infection of the root canal system, is not an exclusively local phenomenon. There is a growing evidence that endodontic infection can also have systemic consequences which emphasizes the importance of its proper treatment. Chemo-mechanical root canal treatment is critical phase of endodontic therapy and should be based on correct biological principles. The goal of mechanical instrumentation and chemical irrigation of root canal system is to remove bacteria and necrotic tissue to treat existing infection or prevent reinfection. It is proven that bacteria have tendency to penetrate dentinal tubules and survive in extreme conditions what makes their complete removal impossible. The complexity of the structure and anatomical irregularities of the root canals, especially in the apical third, further complicate chemo-mechanical process. Proper determination of working length and adequate width are key factors that dictate success. The introduction of new instruments and use of different instrumentation techniques has improved technical quality of root canal treatment. The cleaning and spreading process is faster and easier, but caution is needed to avoid iatrogenic damage such as development of vertical root fracture.