Citrulline (CIT) is an amino acid that is not involved in protein synthesis but that is tightly linked to arginine (ARG) metabolism. CIT displays a very specific metabolism: In the 1980s, Windmuller demonstrated that the small intestine releases CIT, which is mainly taken up by the kidney and metabolized into ARG. Because CIT is not taken up by the liver, this ARG-CIT-ARG cycle can be seen as a means of protecting dietary ARG from liver degradation and of sustaining protein homeostasis. These observations have led to the concept that plasma CIT concentration would be a good marker of intestinal failure in short bowel syndrome. Hence, in massive intestinal resection, citrullinemia is greatly reduced, and this is proportional to the severity of the intestinal disease. This concept was then extended to other situations in which the intestinal function is compromised. The data strongly suggest that CIT may be a conditionally essential amino acid in situations where the intestinal function is compromised. Recent data support this idea. Thus, CIT supplementation is able to restore nitrogen balance, generate large amounts of ARG in rats with short bowel syndrome, and increase muscle protein content (+20%) as well as muscle protein synthesis (+90%) in elderly malnourished rats. Finally, recent data indicate that CIT per se could be able to stimulate muscle protein synthesis. Hence, CIT could play a pivotal role in maintaining protein homeostasis, and the determination of the underlying mechanisms involved in its action should be important for the development of new nutritional strategies in malnourished patients with compromised intestinal functions.