There is good evidence that the experimental manipulation of serotonin causes changes in feeding behavior and that adjustments in feeding and in the nutritional supply bring about responses in the level or activity of serotonin. These data suggest that 5-HT systems in the body mediate nutritional input and the drive to feed. In addition, it is known that serotonin is a phylogenetically primitive neurotransmitter, which may therefore occupy a central role in the relationship between food and brain organization. A framework can be developed by considering the interrelationships among feeding processes (operations of the satiety cascade), peripheral physiological mechanisms, and brain serotonin systems. Two key issues are how nutritional information is transcribed onto brain 5-HT systems and the nature of this information. The neuroanatomical distribution of 5-HT neurons occupy an appropriate position in which to coordinate peripheral physiological and metabolic information, environmental features, and the behavioral response.