Short bowel syndrome occurs when there is insufficient length of the small intestine to maintain adequate nutrition and/or hydration status without supplemental support. This syndrome most frequently occurs following extensive surgical resection of the intestine, and the extent of adaptation depends on the anatomy of the resected bowel and the amount of bowel remaining. Following resection, the intestinal tissue undergoes morphologic and functional changes to compensate for the lost function of the resected bowel. These changes are mediated by multiple interactive factors, including intraluminal and parenteral nutrients, gastrointestinal secretions, hormones, cytokines, and growth factors, many of which have been well characterized in animal models. The amount of small bowel remaining is the most important predictor of adaptive potential; neither structural nor functional adaptative changes have been demonstrated in humans or animal models with more extreme resections resulting in an end-jejunostomy. The current understanding of these processes has led to the recent use of supplemental hormones, such as growth hormone and glucagon-like peptide 2, in intestinal rehabilitation programs and may lead to the development of pharmacologic agents designed to augment the innate adaptive response.