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Ulcerative and blistering oral mucosal lesions are some of the most difficult intraoral conditions to definitively diagnose. These lesions frequently appear on the gingival or oral mucosal tissues before any cutaneous involvement. Because of the persistence of these lesions, the general dentist often requests a consultation from a specialist in oral and maxillofacial pathology, oral medicine, or oral and maxillofacial surgery. These conditions are usually extremely painful. A delay in diagnosis results in poor pain management, the risk of secondary infection of the lesions, and an increased potential for morbidity related to the specific disorder involved. Ulcerative and blistering oral mucosal lesions are characterized by soreness, disfigurement, and morbidity secondary to destruction of the epithelial barrier. Gingival or oral mucosal lesions are often the first sign of these entities and, when gingival, produce a manifestation termed desquamative gingivitis. Desquamative gingivitis is not a definitive diagnosis, but rather a clinical descriptor used when gingival separation is present. The pathogenesis of these diseases is not completely understood. Their diagnoses constitute a challenge for the dentist who needs to understand the pathogenesis of these conditions as well as the means for making an accurate diagnosis, controlling the lesions locally, and referring to a physician for cutaneous, ocular, or other nonoral components of the specific disorder. This article explains the blistering diseases. Extensive reviews of each of these disorders are available to the interested reader, but are outside the scope of this manuscript. Tables are presented to facilitate the clinical differential diagnosis and the understanding of the tissue damage that occurs in these patients. This article also contains the therapy and management options of the oral lesions.