One of the conundrums in today's stress research is why some individuals flourish and others perish under similar stressful conditions. It is recognized that this individual variability in adaptation to stress depends on the outcome of the interaction of genetic and cognitive/emotional inputs in which glucocorticoid hormones and receptors play a crucial role. Hence one approach towards understanding individual variation in stress coping is how glucocorticoid actions can change from protective to harmful. To address this question we focus on four hypotheses that are connected and not mutual exclusive. First, the classical Glucocorticoid Cascade Hypothesis, in which the inability to cope with chronic stress causes a vicious cycle of excess glucocorticoid and downregulation of glucocorticoid receptors (GR) in the hippocampus triggering a feed-forward cascade of degeneration and disease. Second, the Balance Hypothesis, which takes also the limbic mineralocorticoid receptors (MR) into account and proposes that an integral limbic MR:GR imbalance is causal to altered processing of information in circuits underlying fear, reward, social behaviour and resilience, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and impairment of behavioural adaptation. The MR:GR balance is altered by gene variants of these receptor complexes and experience-related factors, which can induce lasting epigenetic changes in the expression of these receptors. A particular potent epigenetic stimulus is the maternal environment which is fundamental for the Maternal Mediation Hypothesis. The outcome of perinatal gene x environment interaction, and thus of MR:GR-mediated functions depends however, on the degree of 'matching' with environmental demands in later life. The Predictive Adaptation Hypothesis therefore presents a conceptual framework to examine the role of glucocorticoids in understanding individual phenotypic differences in stress-related behaviours over the lifespan.