Post-operative pain is defined as pain of any degree that occurs after the initiation of root canal treatment, while endodontic flare-up has been defined as the onset or continuation of pain and/or swelling after endodontic treatment. It is well perceived that pretreatment pain predicts post-treatment pain and is consistent with several endodontic studies. While post-operative pain following an endodontic procedure is distressing for the patient, particularly when he or she arrives asymptomatic to the dental office, it is professionally unacceptable for the clinician. According to modern concepts, pain control is a foreseeing action and early prevention whereas earlier concepts of control were implemented when errors were detected or anticipated. According to recent studies, pain perception and modulation is genetically enhanced and altered in patients with persistent post endodontic pain. Here, we present information form the literature regarding predictors of postoperative pain, risk factors, and management. The objective is to try to come into the conclusion that prevention of post-operative pain is the key for successful pain management.