The term “interface dermatitis” (ID) involves a specific histological inflammatory pattern that is characterized by a cytotoxic lymphocytic infiltration and a hydropic degeneration of the basal epidermal layer. ID is typically seen in autoimmune skin disorders such as lichen planus (LP), cutaneous lupus erythematosus (CLE), and may also appear during immune reactions against drugs, viruses, and tumors. Recent studies have shown that the type-I IFN system is involved in cutaneous autoimmune diseases characterized by ID. IFNs induce the expression of proinflammatory cytokines and chemokines, which support the cellular immune response. The role of IFNs in ID is supported by a close morphological association between the expression pattern of IFN-inducible proteins and the distribution of CXCR3+ lymphocytes. The IFN-inducible chemokine CXCL10 is expressed in exactly those areas where cytotoxic lymphocytes invade the basal epidermis and cause keratinocyte death. A similar picture can be found in early herpes simplex viral skin lesions and viral warts, but also in “lichenoid” actinic keratosis and invasive squamous cell carcinoma. These data suggest that ID morphologically reflects a common IFN-driven cytotoxic attack affecting the basal keratinocytes under different conditions, which is important for antiviral and antitumor immune response, but is inappropriately activated in autoimmune skin disorders.