The gastrointestinal tract is the largest endocrine organ that produces a broad range of active peptides. Mucosal changes during inflammation alter the distribution and products of enteroendocrine cells (EECs) that play a role in immune activation and regulation of gut homeostasis by mediating communication between the nervous, endocrine and immune systems. Patients with inflammatory bowel disease (IBD) typically have altered expression of chromogranin (CHG)-A (CHGA), a major soluble protein secreted by EECs that functions as a pro-hormone. CHGA gives rise to several bioactive peptides that have direct or indirect effects on intestinal inflammation. In IBD, CHGA and its derived peptides are correlated with the disease activity. In this review we describe the potential immunomodulatory roles of CHGA and its derived peptides and their clinical relevance during the progression of intestinal inflammation. Targeting CHGA and its derived peptides could be of benefit for the diagnosis and clinical management of IBD patients.