Chronic pain that arises or persists after endodontic treatment is an undesirable condition that requires proper diagnosis in order to be adequately approached. Some so-called 'mysterious' cases are usually related to limited knowledge or clinical inexperience, but inadequacies of diagnostic tools can also lead to misdiagnosis and confusion. The main causes of chronic post-treatment pain not always promptly recognised are outlined in this paper and include: i) persistent/secondary intraradicular infection; ii) persistent inflammation-undetected lesion; iii) unnoticed overfilling; iv) missed canals; v) vertical root fracture or crack; vi) wrong tooth; vii) non-odontogenic pain; and viii) central sensitisation (risk factors: preoperative pain, previous painful treatment). By having all of these possible causes in mind, clinicians may create a checklist for the possible reason(s) for pain in difficult individual cases and act proactively to offer the best therapeutic solution. Keywords: apical periodontitis, cone-beam computed tomography, endodontic treatment, persistent infection, post-treatment pain, secondary infection