Despite significant advances in dentistry, pain after root canal therapy is still of concern for both patients and dentists. Although the pain does not necessarily indicate endodontic failure, relief of this pain is very important for the patient. In addition, the ability to prevent or control this pain is an important factor for a dentist's professional success. Pain in endodontics is usually due to a periapical inflammatory reaction, which occurs before, during, or following various endodontic procedures. The severity of the inflammatory response is variable, depending on local and systemic factors. The cause of pain and/or swelling in endodontic therapy is not always clear. There are numerous factors accounting for endodontic pain, suggested by researchers. These factors may be classified into three main groups: Iatrogenic factors, patient factors, and intracanal factors. The most important factor in controlling post-endodontic pain is to have sufficient knowledge about the causes of the problem and to prevent them. The aim of this review article is to discuss factors involved in post-endodontic pain and offer techniques, including the use of analgesics, to prevent or relieve the pain.