<jats:title>ABSTRACT</jats:title><jats:p>Glucagon‐like peptide‐2 (GLP‐2) is an intestinally derived hormone that enhances intestinal growth, digestion, absorption, barrier function, and blood flow in healthy animals as well as preventing damage and improving repair in preclinical models of enteritis and colitis and following massive small bowel resection. These beneficial effects of GLP‐2 on the intestinal tract are largely recapitulated in humans with intestinal failure. The high‐specificity of this peptide for the intestinal tract and the development of degradation‐resistant, long‐acting GLP‐2 receptor agonists have rapidly led to clinical implementation of GLP‐2‐based therapy for the treatment of patients with short bowel syndrome, with few reported side effects. This comprehensive review covers the biology of GLP‐2, from the control of proglucagon gene expression and the posttranslational processing of proglucagon to liberate GLP‐2 to the regulation of GLP‐2 secretion from the intestinal L cell, and from the mechanism of action of GLP‐2 through its highly localized receptor to the biological activities of GLP‐2 in the intestine and other restricted locations in the body, under physiological conditions as well as in animal models of intestinal disease and in patients with short bowel syndrome. Collectively, the history of GLP‐2 serves as a remarkable bench‐to‐bedside story of translational medicine. © 2017 American Physiological Society.<jats:italic>Compr Physiol</jats:italic>8:1185‐1210, 2018.</jats:p>