Glucocorticoids are key elements in the maintenance of an organism's homeostasis, a dynamic balance that is constantly challenged by internal and external stressors. Chronic exposure to elevated glucocorticoids may induce profound effects on an individual's physical and mental well-being. Therefore, a complex neuroendocrine system, the limbic-hypothalamo-pituitary-adrenocortical (LHPA) axis, exists to regulate glucocorticoid homeostasis. Dysregulation of the LHPA axis has been linked to numerous psychiatric disorders, including eating disorders, anxiety, depression, posttraumatic stress disorder, memory impairment, neurodegenerative disorders, and even Alzheimer disease. At a molecular level, the actions of glucocorticoids are mediated by two different cytoplasmic receptors, the mineralocorticoid receptor and the glucocorticoid receptor. These corticosteroid receptors are heteromeric complexes found in dynamic association with a still growing number of chaperone proteins and other factors mediating their actions. Because this dynamic association is extremely sensitive to changes in cellular environment, energy, and metabolic state, we hypothesize that these corticosteroid receptors act as "sensor" signal transducers critical for homeostasis. In this review, we focus on the interplay among protein folding, transport, and function of the corticosteroid receptors at the cellular level, which provides a foundation for understanding the pathogenesis of glucocorticoid resistance or hypersensitivity, causing imbalances in the LHPA axis, and possibly triggering psychiatric disorders.