This clinical review will summarize the available data regarding the role of mineralocorticoid receptors (MRs) on the hypothalamus-pituitary-adrenal (HPA) axis control in physiological and pathological conditions and in the memory processes involved in the control and appraisal of a stress event. MRs are predominantly expressed in the limbic structures, with the hippocampus being the main localization, although MRs are also found at the hypothalamic level. It is known that hyppocampal MRs control the proactive feedback involved in the maintenance of the basal HPA activity, mainly at the nadir of the circadian rhythm. In physiological conditions, the administration of pharmacological doses of both MR antagonists and agonists is able to interact with the HPA activity, modifying the quiescent phase-nadir of the circadian rhythm, although some data in the literature do not support these observations. Also, in a physiological condition such as aging, an enhanced HPA axis activity is found in the time window, when MRs are predominantly occupied by cortisol circulating levels, possibly reflecting an MR impairment in this period of life. In pathology, major depression has been correlated to MR qualitative-quantitative alterations which could reflect differences on psychological and physiological responses, possibly predicting psychopathologies. Most of the remarks reported in this review seem to indicate, in agreement with animal data, a role played by MRs in the delicate control of the HPA axis in humans and the possible predisposition to the development of pathologies in case of their alterations.