Adrenomedullin (AM) is a 52 amino acid, multifunctional hormone. It is expressed in many tissues of the human body including the pancreas, where it is mainly localized to the periphery of the islets of Langerhans and specifically to the pancreatic polypeptide-expressing cells. The AM receptor, a complex formed by calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs), and the recently discovered AM-binding protein, complement factor H (fH), are expressed in the insulin-producing beta-cells. The colocalization of these key elements of the AM system in the endocrine portion of the pancreas implicates AM in the control of both normal and altered pancreatic physiologies. AM inhibits insulin secretion both in vitro (isolated rat islets) and in vivo (oral glucose tolerance test in rats) in a dose-dependent manner. The addition of fH to isolated rat islets produces a further reduction of insulin secretion in the presence of AM. Furthermore, AM is elevated in plasma from patients with pancreatic dysfunctions such as type 1 or type 2 diabetes and insulinoma. Using a diabetic model in rats, we have shown that AM increases circulating glucose levels whereas a blocking monoclonal antibody against AM has the opposite effect and improves postprandial recovery. Such experimental evidence implicates AM as a fundamental factor in maintaining insulin homeostasis and normoglycemia, and suggests the implication of AM as a possible causal agent in diabetes. Further investigation focused on the development of blocking agents for AM could result in new treatments for pancreatic AM-related disorders.