Multiple systemic diseases affect the oral mucous membranes and may cause a variety of signs and symptoms that are difficult to distinguish from other primary pathologic processes that arise in the oral cavity. These systemic diseases include, but are not limited to, hematologic and endocrine abnormalities along with gastrointestinal and dermatologic diseases. Common presentations include mucosal ulcerations and erosions, vesicles and bullae, macroglossia, atrophic glossitis, leukoplakia, and petechial and ecchymotic lesions. These clinical presentations are similar to those that occur in patients with various primary oral mucosal diseases. Therefore, an understanding of the oral manifestations of systemic diseases is important in order to ensure that an accurate diagnosis is established and appropriate patient care is instituted. These clinical correlates also serve as the basis for investigative efforts to better define the mechanisms of oral tissue injury.