Desquamation of the gingiva is a sign that may be encountered in clinical practice. Various diseases can affect the gingival tissues. Mild desquamation that is localized may be associated with mechanical irritation or induced by trauma. Moderate to severe generalized desquamation associated with ulceration and erythema may be indicative of a more serious systemic condition. Although often overlooked, mucocutaneous diseases frequently present with gingival desquamation as an early presenting symptom. The most common mucocutaneous diseases that affect the oral cavity are lichen planus, pemphigus, and mucous membrane pemphigoid. This article reviews the etiology, signs and symptoms, and therapies for these disorders. Increased knowledge of mucocutaneous diseases can help the clinician recognize these disorders and enable the patient to receive appropriate therapy.