Glucocorticoids are members of steroid hormones that are biosynthesized in the intermediate cellular zone of the adrenal cortex (zona fasciculata) and released into the peripheral blood as final products of the hypothalamic-pituitary-adrenal (HPA) axis, as well as under the control of the circadian biologic system. These molecules regulate every physiologic function of the organism as they bind to an almost ubiquitous hormone-activated transcription factor, the glucocorticoid receptor (GR), which influences the rate of transcription of a huge number of target genes amounting to up to 20% of the mammalian genome. The evolving progress of cellular, molecular and computational-structural biology and the implication of epigenetics in every-day clinical practice have enabled us a deeper and ever-increasing understanding of how target tissues respond to natural and synthetic glucocorticoids. In this chapter, we summarize the current knowledge on the structure, expression, function and signaling of the human glucocorticoid receptor in normal and pathologic conditions.