Immune-mediated and autoimmune diseases of the skin often present with oral cavity involvement. Autoimmune subepidermal blistering diseases and pemphigus vulgaris are classic examples. While the primary lesions (vesicles and bullae) are relatively specific, these fragile lesions evolve rapidly into erosions and ulcers, which are lesion types that overlap with many diseases. Furthermore, some immune-mediated diseases such as severe adverse drug reactions, lupus diseases, canine uveodermatological syndrome, and vasculitis, may or may not involve the oral cavity, and often nonoral clinical manifestations are more diagnostic. In these situations, disease knowledge combined with signalment, lesion distribution, and history help to narrow the differentials. Surgical biopsy is required for confirmation in most diseases, while immunosuppressive treatments most typically involve glucocorticoids with or without nonsteroidal immunosuppressants.