Many diseases that have a systemic distribution may involve the gastrointestinal (GI) tract and liver. Furthermore, diseases that usually manifest within one extra-gastrointestinal organ or system may also involve the GI tract, either directly or as a result of treatment for the extra-GI disease. This chapter focuses initially on five systemic diseases that can have GI manifestations: sarcoidosis, amyloidosis, mast cell diseases, IgG4-related disease, and Behçet’s disease, and then discusses diseases with cutaneous manifestations and their effect(s) on the GI tract. Systemic diseases may become manifest within the GI tract in the context of a known condition. When this occurs, the cause of the GI disease may be obvious. Alternatively, the GI tract features may represent the presenting phase of the disease, which could already be active but subclinical at other sites. The differential diagnosis of certain histopathological features associated with GI tract manifestations of systemic disease, e.g. granulomas, may be wide. Therefore, careful clinicopathological correlation is essential. Finally, treatments for some extra-GI conditions may cause GI-related side effects, e.g. methotrexate therapy for psoriasis.