The stress system orchestrates brain and body responses to the environment. Cortisol (in humans) or corticosterone (in rodents) are important mediators of the stress system. Their action-in concert-is crucial for individual differences in coping with other individuals, which in turn depend on genetic- and experience-related factors. The actions exerted by cortisol and corticosterone have an enormous diversity. They include the regulation of rapid molecular aggregations, membrane processes, and gene transcription. In the latter transcriptional regulation, the corticosteroid hormones have two modes of operation. One mode is mediated by high-affinity mineralocorticoid receptors (MRs), which control gene networks underlying stabilization of neuronal activity as determinant for the sensitivity to trigger immediate responses to stress organized by corticotrophin-releasing hormone (CRH)-1 receptor. Whereas disturbance of homeostasis is prevented by MR-mediated processes, its recovery is facilitated via the low-affinity glucocorticoid receptors (GRs) that require stress levels of cortisol. GRs promote in coordination with CRH-2 receptors and the parasympathetic system behavioral adaptation and enhances storage of energy and information in preparation for future events. The balance in the two stress system modes is thought to be essential for cell homeostasis, mental performance, and health. Imbalance induced by genetic modification or stressors changes specific neural signaling pathways underlying cognition and emotion. This yin-yang concept in stress regulation is fundamental for genomic strategies to understand the mechanistic underpinning of corticosteroid-induced stress-related disorders such as severe forms of depression.