The mammalian gastrointestinal mucosa is a rapidly self-renewing tissue in the body, and its homeostasis is preserved through the strict regulation of epithelial cell proliferation, growth arrest, and apoptosis. The control of the growth of gastrointestinal mucosa is unique and, compared with most other tissue in the body, complex. Mucosal growth is regulated by the same hormones that alter metabolism in other tissues, but the gastrointestinal mucosa also responds to a host of events triggered by the ingestion and presence of food within the digestive tract. These gut hormones and peptides regulate the growth of the exocrine pancreas, gallbladder epithelium, and the mucosa of the oxyntic gland region of the stomach and the small and large intestines. Luminal factors (nutrients or other dietary factors, secretions, and microbes), which occur within the lumen and distribute over a proximal-to-distal gradient, are also crucial for the maintenance of the normal gut mucosal growth and could explain the villous height-crypt depth gradient and variety of adaptations since these factors are diluted, absorbed, and destroyed as they pass down the digestive tract. Recently, intestinal stem cells and polyamines are shown to play an important role in the regulation of gastrointestinal mucosal growth under physiological and various pathological conditions. In this chapter, we highlight key issues and factors that control gastrointestinal mucosal growth, with special emphasis on the mechanisms through which epithelial renewal is regulated by polyamines at the cellular and molecular levels.