Ghrelin, a hormone produced by the stomach, is generally associated with feeding responses and the regulation of food intake. Recent evidence, however, suggests that ghrelin is also a stress hormone, given that it is released following acute and chronic stressors. The present study examined the role of ghrelin in producing normal metabolic and neurochemical responses to chronic stress. This was achieved by examining these responses in mice with targeted deletions of the ghrelin receptor gene (GHSR KO mice), and comparing them with the same responses in their wild-type (WT) littermates. As expected, WT stressed mice decreased their caloric intake, body weight gain and caloric efficiency while maintaining adiposity. GHSR KO mice, however, did not show these alterations despite having normal glucocorticoid responses to stress. In parallel with these changes, chronic unpredictable stress caused changes in norepinephrine, dopamine and serotonin in a number of brain regions. Of these, norepinephrine neurotransmission in the arcuate nucleus and prefrontal cortex was differentially altered in GHSR KO mice. Within the nucleus acumbens, dopamine utilization was increased in WT mice but not in GHSR KO mice. Finally, there were strain differences in serotonin neurotransmission that may explain interstrain body weight and adiposity differences. These results suggest that the metabolic changes necessary to deal with the energetic challenge presented by repeated exposure to stressors do not occur in GHSR KO mice, and they are discussed within the context of the potential vulnerability to stress-induced pathology.