The prevalence rates of obesity and metabolic syndrome are on the rise in the United States. Epidemiological surveys suggest that the rates of these medical conditions are especially high among persons with psychiatric disorders, including post-traumatic stress disorder (PTSD). A variety of factors are thought to contribute to the risk for metabolic syndrome, including excessive caloric intake, decreased activity and energy expenditure, use of certain medications, stress and genetic influences. Recent research demonstrates that stress, acting through the neuropeptide Y (NPY) and glucocorticoid systems, potentiates the development of obesity and other aspects of metabolic syndrome in mice fed a high caloric, fat and sugar diet. Alterations in the NPY and glucocorticoid systems also impact behavioral adaptation to stress, as indicated by studies in animals and persons exposed to severe, life-threatening or traumatic stress. The following review examines the biology of the NPY and neuroactive steroid systems as physiological links between metabolic syndrome and PTSD, a paradigmatic neuropsychiatric stress disorder. Hopefully, understanding the function of these systems from both a translational and systems biology point of view in relation to stress will enable development of more effective methods for preventing and treating the negative physical and mental health consequences of stress.