The balanced interaction of the various humoral and neural mediators that serve to contain stress reactions in the acute phase and in the management of the late recovery phase is of crucial importance for defense of homeostasis and health. Imbalance due to inadequate or excessive operation of these stress system mediators may compromise resilience and promote a phenotype vulnerable to stress-related disease. The importance of a ‘balance’ in the concentration and action of stress mediators is illustrated by the glucocorticoid hormone (cortisol or corticosterone). The hormone operates both in the fast and slow modes of the response to stress and produces lasting effects in preparation of future events. The two complementary modes of operation of cortisol/corticosterone depend on the phase and context of the stress response, the bio-availability of the hormone and the target cell response. The molecular basis of this dual mode of operation of cortisol is formed by two types of receptors – mineralocorticoid (MR) and glucocorticoid (GR) receptors – that bind in vivo cortisol and corticosterone with an order of magnitude difference in affinity. Thus, a concept has evolved in which MR and GR mediate the dual mode of operation of cortisol in limbic brain to coordinate the onset and termination of the physiological and behavioural adaptations to the stressor. MR and GR belong to interacting signalling networks that underlie adaptive processes from appraisal of novel situations and prediction of upcoming events to recovery from the challenge and storage of the experience in the memory. Thus questions to be addressed are: which factors determine balanced MR/GR interaction? How is MR/GR imbalance related to a vulnerable phenotype? How does the MR/GR balance contribute to individual differences in vulnerability? Which biomarkers can reveal imbalance in stress system operation related to MR and GR?