The adrenal gland synthesizes a group of well characterised steroid hormones with powerful physiological regulatory effects across the human body. One of these is cortisol that is a strong agonist to both the glucocorticoid and mineralocorticoid receptors. Both proteins are well characterised nuclear receptors that act primarily as ligand-modulated transcriptional regulators of the genome in a vast array of cell types within the body. The glucocorticoid receptor (GR) also elicits rapid non-genomic effects via monomer interactions with many proteins in the cytosol. Functional roles of GR signalling include regulation of embryo development, integrated metabolism, immune suppression, neuronal modulation and a range of other anti-stress responses. Gene-targeted mouse models have defined tissue and cell-type-specific functional roles across the body including the brain, metabolic tissues and the immune system. Synthetic steroid ligands and non-steroidal drugs have been developed to treat a wide range of clinical diseases and conditions. These will be described and discussed. Selective glucocorticoid receptor modulators represent an expanding list of potential drugs for clinical use. Newer novel prodrugs to selectively target the GR are also under development. Newer concepts of signalling ‘unknowns’ for the GR include detection of multimeric receptor complexes in the nucleus, the potential formation of heterodimers with the MR and perhaps other steroid hormone receptors. Finally, the integration of genomic and non-genomic GR signalling responses within a cell for a final cellular change remains a challenge to understand. Current understanding of these mechanisms and their future clinical impact in vivo with be discussed.