Systemic diseases have many different presentations, including imaging findings in the bowel. Recognizing the imaging findings in these diseases is important in making the correct diagnosis. Although certain imaging features overlap, knowledge of specific findings along with the clinical presentation aid in narrowing the differential or in making an imaging diagnosis. The pictorial review will focus on the gastrointestinal manifestations of systemic diseases, including amyloidosis, angiotensin converter enzyme inhibitor-induced angioedema, celiac sprue, distal intestinal obstruction syndrome, graft-versus-host disease, hemolytic uremic syndrome, hemophilia, Henoch-Schönlein purpura, intestinal lymphangiectasia, mastocytosis, scleroderma, systemic lupus erythematosus, Wegener's granulomatosis, and Whipple's disease. The aforementioned diseases can be subdivided based upon the underlying process leading to the disease. The diseases discussed are categorized into autoimmune, infiltrative, treatment related, congenital/hereditary, and infectious etiologies.