Glucocorticoids have a broad array of life-sustaining functions, such as for the maintenance of the basal- and stress-related organ homeostasis. They are also frequently used as therapeutic compounds for many pathologic conditions. Thus, changes of tissue sensitivity to glucocorticoids play important roles in the physiologic conditions and are associated with and influence the course of numerous pathologic states. Changes in tissue glucocorticoid sensitivity may present on either side of an optimal range, respectively as glucocorticoid resistance or hypersensitivity, and may be generalized or tissue-specific. Recent insights into the mechanisms of the glucocorticoid receptor (GR) action indicated that the glucocorticoid signaling system is highly stochastic. Indeed, numerous factors contribute to the hormonal action at each step of the GR signaling cascade, such as ligand availability, receptor isoform expression, intracellular circulation, promoter association, attraction of cofactors, and finally clearance of the receptor from the target genes. Importantly, these regulatory mechanisms appear to be functional in tissue-, gene- and cellular biologic state-specific fashions. As an example of such phase-specific factors, we discussed influence of the cyclin-dependent kinase 5 to the GR transcriptional activity, which specifically functions in the central nervous system and may thus play an important role in the regulation of glucocorticoid action in this organ.