Gastrointestinal disorders, such as irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD, including Crohn’s disease and ulcerative colitis), affect 10–15% of the global population resulting in a substantial socioeconomic burden on our society.[1] Mucosal biofilms are mucus-adherent prokaryotic communities embedded in a protective layer of extracellular substances, displaying high antibiotic resistance,[2] and occur in 57% of IBS patients and 34% of ulcerative colitis patients.[3] Antimicrobial peptides (AMPs) of natural origin evolved for their activity to combat bacteria,[4] representing therapeutic opportunities for treating infectious diseases. However, the full potential of such AMPs against gut mucosal biofilms has not been revealed yet. Our approach focuses on developing gut biofilm-targeting peptides, including (i) synthesis of AMPs from diverse natural sources, (ii) screening for biofilm-specific activity against bacterial isolates from biofilm-positive patients, and (iii) chemical strategies to improve our AMP leads’ gut stability and therapeutic window. Here, we report our latest results in developing gut-specific antibiofilm peptides to treat mucosal biofilms in patients with gastrointestinal disorders.