Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive, catecholaminergic and immunomodulation, followed by a reset via cortisol. Stress system components, the sympathoadrenomedullary system, hypothalamic-pituitary-adrenal axis and limbic brain structures are implicated in many chronic diseases, through the development of an altered homeostatic state, allostasis. Consequent “primary stress system disorders” were popularly accepted, with phenotypes based on conditions including Cushing’s syndrome, pheochromocytoma, and adrenal insufficiency. Cardiometabolic and major depressive disorders are candidates for hypercortisolaemic aetiology, contrasting the “hypocortisolaemic symptom triad” of stress sensitivity, chronic fatigue, and pain. However, acceptance of chronic stress aetiology requires cause-and-effect associations, and practical utility such as therapeutics altering stress system function. Inherent predispositions to stress system perturbations may be relevant. Glucocorticoid receptor (GR) variants have been associated with metabolic/neuropsychological states. The SERPINA6 gene encoding corticosteroid-binding globulin (CBG), was the sole genetic factor in a SNP-GWAS linkage study of morning plasma cortisol, a risk factor for cardiovascular disease, with alterations in tissue-specific GR-related gene expression. This allows studies of genetically predicted cortisol levels in large population studies to determine the effect of cortisol in a host of diseases where cortisol may be relevant. These mendelian randomisation studies obviate the problem of "cause or effect" of altered cortisol concentrations in diseases. Genetically predicted high cortisol concentrations are associated with hypertension and anxiety, and low CBG concentrations/binding affinity, with the hypocortisolaemic triad. Acquired CBG deficiency in septic shock results in 3-fold higher mortality when hydrocortisone administration produces equivocal results, consistent with CBG’s role in spatiotemporal cortisol delivery. We propose some stress system disorders result from constitutional stress system variants rather than stressors themselves. Altered CBG: cortisol buffering may influence interstitial cortisol ultradian surges leading to pathological tissue effects, an example of stress system variants contributing to stress-related disorders.