Glucocorticoids (GCs) are the most effective anti-inflammatory drugs in current clinical settings, yet their genomic modes of action are poorly understood. GCs bind to the Glucocorticoid Receptor (GR), which acts as a transcription factor to control gene expression in the immune system. Understanding the molecular mechanism that delineates gene repression of pro-inflammatory target genes from gene activation of metabolic genes will help to improve GC therapy and overcome adverse effects.