Space travelers experience a flight duration-dependent loss in weight and body mass while in a microgravity environment, despite the absence of increased energy expenditure. Anorexia in space can lead to in-flight caloric deficits of 1330 kcal per 70 kg astronaut per day in the presence of abundant food and has a critical effect on endurance and performance. Microgravity, alterations in the light-and-dark cycle, and exposure to radiation energy are the environmental stresses believed to influence appetite, food intake, and gastrointestinal function during space flight. Review of data and recent studies in rodents during microgravity showed a release of stress hormones and complex neuroendocrine and physiologic changes involving the modulation of hypothalamic activity, food intake-related hormones, and cytokines. The shift of dietary preference to carbohydrates, which occurs in astronauts, denotes a stress physiologic response and augments free-plasma tryptophan concentration in the brain, the precursor of the potent anorexic agent, serotonin (5-HT). Alterations of other neuroendocrine mediators, including corticotropin-releasing factor (CRF), coordinate the stress response, leading to a decrease in appetite and gastrointestinal function. Our laboratories used the antiorthostatic tail-suspension technique to successfully mimic some of these anorexia-related stress responses and to directly demonstrate the role of 5-HT in microgravity-related decreased food intake and delayed gastric emptying. Further rodent studies from our laboratories demonstrated the adverse effect of altered dark-and-light cycles on food intake and body weight. Radiation energy, through its documented effects on appetite, probably contributes to the decreased caloric intake by astronauts. Modulation of hypothalamic activity, 5-HT, and CRF play a critical role in anorexia related to microgravity and circadian rhythm alterations. Specific gene knockout mice (e.g., 5-HT or CRF and their respective receptors) may prove fruitful in defining the pathways by which anorexia in space occurs. An understanding of these pathophysiologic problems as they relate to appetite, food intake, gastric emptying and gastrointestinal function, sufficiently to derive successful practical solutions, may lead to a quantitative enhancement of physiologic well-being and performance status, serving as a productive countermeasure in space.