The ability to respond to changes in the external and internal environments is a fundamental characteristic of intestinal structure and function. We compared the responses of the rat proximal and distal small intestine to the stresses of fasting and refeeding in the rat. In the duodenum, 3 days of starvation caused villus and crypt hypoplasia, reduced incorporation of [3H]thymidine into crypt cells, decreased cell migration rate on the villus, and lowered specific and total activities of several cellular enzymes. These changes were reversed by 1 day of refeeding. In contrast, mucosal hypoplasia did not occur in the ileum during fasting, and the specific activities of the disaccharidases were increased after 3 days of starvation. However, ileal [3H]thymidine incorporation, thymidine kinase activity, and ornithine decarboxylase activity decreased during starvation. These effects were also reversed by refeeding. The results of these studies illustrate differing responses for the proximal and distal small intestine and suggest the presence of distinctly differing mechanisms for the control of their mucosal mass and enzyme activities.