Most of periapical radiolucencies are the result of inflammation such as pulpal disease due to infection or trauma. Not all radiolucencies near the tooth root are due to infection. Odontogenic or non odontogenic lesions can over impose the apices of teeth. Disease related to the tooth may spread to adjacent tissues, including the sinuses, orbits, deep fascial spaces of the neck, and intracranial structures, and result in a significant increase in patient morbidity and even mortality. Periapical radiolucency near the apices may be seen in the setting of other diseases including systemic conditions, benign or malignant neoplasms. Although imaging findings for these lesions can include periapical lucent components, awareness of the varied secondary imaging features can aid the dentist in developing an accurate differential diagnosis. Familiarity with the radiological features and differential diagnoses of diseases or conditions that cause radiolucency around the apex of the tooth results in appropriate referral and prompt diagnosis, management, and treatment, and can prevent unnecessary additional imaging or intervention. In addition, early recognition and appropriate treatment of infectious, benign or malignant processes will result in improved clinical outcomes and a decrease in morbidity and mortality.