The successful outcome of endodontic treatment is dependent on the immune response and the reparative potential of the individual. Alteration in the host immune response is a common characteristic shared by both apical periodontitis and systemic diseases. Although infection-induced periapical lesions occur in a localized environment, numerous epidemiologic studies in the last few decades have investigated the potential association between endodontic disease pathogenesis and systemic diseases. The goal of this review is to identify common systematic factors and discuss the effect they may or may not have on the prognosis and outcome of endodontic therapy.