Brain mineralocorticoid receptors (MR) mediate effects of aldosterone in relation to salt homeostasis, and of glucocorticoid stress hormones corticosteroids in the context of stress adaptation. Brain stem MRs respond to aldosterone, while forebrain MRs mediate rapid and delayed MR-mediated glucocorticoids effects in conjunction with the glucocorticoid receptor. MR-mediated effects depend on gender, genetic variations and environmental influences. Disturbed MR activity by chronic stress or in certain (endocrine) diseases can cause deleterious effects on affective state, cognitive and behavioural function in susceptible individuals. High MR activation may have protective effects in healthy individuals, whereas dysregulated high MR activity during a stress response would require treatment with mineralocorticoid receptor antagonists (MRAs). Here, we discuss recent pharmacological and genetic developments, from the molecular underpinnings of MR signaling and function, to pharmacological interventions in the clinic. Improved understanding of MR dependent pathways will help to improve glucocorticoid therapy, unwanted side effects and psychiatric symptoms.