The data presented demonstrates a correlation of plasma cortisol levels and receptor sensitivity with mammalian longevity and replicative senescence; observations possibly related to the influence of cortisol on chaperone expression and cancer resistance. The molecular chaperones are essential structural and functional elements of the steroid hormone receptors, and serve to modify the sensitivity of the cortisol receptor. Cushing's syndrome illustrates the harmful effects of sustained high levels of cortisol; thus probably the circadian and stress-induced variations, as well as the hormone levels are important for the homeostatic effects of the steroid hormones in counteracting the age related decline of chaperone response and of possible importance for the evolution of mammalian longevity.