Persistent apical periodontitis (AP) creates a clinical dilemma. AP is the most important factor to influence the success of endodontic treatment. Under controlled clinical conditions, in the presence of AP, the potential for a favorable outcome for primary and secondary root canal treatment (RCT) is 75% to 80%. The size of the lesions, presence of sinus tracts or perforations, quality of filling and coronal restoration has an influence on the treatment outcome almost as the health and conditions of the immune system of the patient. Furthermore, genetic polymorphism and biologic modifiers put patients at risk for severe responses to endodontic infection and higher susceptibility to persistent AP by creating a stronger immune-inflammatory reaction at the periapex of a tooth. These conditions should be addressed to the endodontists to enable them to alter treatment and expectations consequently, and to use new protocols when needed. Last, it may be hypothesized that, in addition to the proper antibacterial approach, the modulation of host immune response may enhance healing of AP.