Diabetes mellitus is a chronic disease with serious health consequences. The association between diabetes and periodontal disease is well documented. However, the progression and healing of endodontic infections in diabetic patients has not been adequately studied. In this review, diabetes mellitus is explored as a potential modulating factor of endodontic pathosis. Recent data on the relationship between the clinical presentation of pulpal and periradicular disease, as well as the outcome of endodontic treatment in diabetic and nondiabetic patients, are presented. Diabetics who present for endodontic treatment, particularly those with periradicular pathosis, may have increased perioperative symptoms. Cases with preoperative periradicular lesions are less likely to be determined successful two years or longer postoperatively if the patient reports a history of diabetes. Studies examining the pathogenesis of periradicular lesions in mouse models with uncontrolled type 1 diabetes suggest that the lesion size may be increased and the animals have increased serious sequelae. Preliminary findings suggest that some bacterial species may be more prevalent in necrotic pulp of diabetic than nondiabetic patients. More studies are needed to further explore the microbiology of endodontic infections and to determine effective treatment strategies in both diabetic and nondiabetic patients.