Proteases are widely distributed in the human body and are crucially involved in the modulation of physiological processes in the gastrointestinal (GI) tract. They also have a major role in the etiology and the course of GI diseases. This review discusses the pharmacology of proteases and medical application of their inhibitors in the GI tract. In particular, we focus on metabolic disorders, such as diabetes type 2, inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS) and abdominal pain. Based on recent papers in the field of pharmacology and documented clinical trials, we suggest future treatment options employing protease inhibitors. Copyright © 2013 Elsevier Ltd. All rights reserved.