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Fear of the pain associated with endodontic treatment remains a formidable hurdle for patients and dentists. Our culture and the media reinforce the belief that endodontics means pain. The result can be a patient's refusal to have endodontic treatment and opt instead for an extraction. In 2002, when the article “Clinical Strategies for Managing Endodontic Pain” was published in Endodontic Topics, the focus was on the diagnosis of pain, clinical procedures directed at the relief of pain, and the role of anxiety. Since then, it has become clear that other factors may predispose some patients to pain. Clinicians have had the experience of providing endodontic treatment for two patients of the same age and sex with similar teeth. Despite using an identical clinical approach, the patients' responses are remarkably different. While one does not require postoperative analgesics, the other has severe pain/swelling requiring an emergency visit. Although iatrogenic factors are always a possibility, there is increasing evidence that a patient's genetic make-up, sex, and level of anxiety may affect their response to treatment. Patients' responses to an analgesic may also vary and these too may be linked to genetic variations or issues associated with a patient's sex or level of anxiety. This article reviews recent evidence in those areas as well as the use of cone beam computed tomography (CBCT) and its impact on diagnosis. Differentiation of odontogenic and non-odontogenic pain is also discussed. Therapeutics has undergone significant change. Current clinical research concerning the combined use of ibuprofen/acetaminophen is reviewed.