Glucocorticoids (GCs) exert their anti-inflammatory and antiproliferative effects principally by inhibiting the expression of cytokines and adhesion molecules. Mechanistically, GCs diffuse through the cell membrane, and bind to their inactive cytosolic receptors (GRs), which then undergo conformational modifications that allow for their nuclear translocation. In the nucleus, activated GRs modulate transcriptional events by directly associating with DNA elements, compatible with the GCs response elements (GRE) motif, and located in variable copy numbers and at variable distances from the TATA box, in the promoter region of GC-responsive genes. In addition, activated GRs also acted by antagonizing the activity of transcription factors, in particular nuclear factor-κB (NF-κB), by direct and indirect mechanisms. GCs induced gene transcription and protein synthesis of the NF-κB inhibitor, IκB. Activated GR also antagonized NF-κB activity through protein-protein interaction involving direct complexing with, and inhibition of, NF-κB binding to DNA (Simple Model), or association with NF-κB bound to the κB DNA site (Composite Model). In addition, and according to the Transmodulation Model, GRE-bound GR may interact with and inhibit the activity of κB-bound NF-κB via a mechanism involving cross-talk between the two transcription factors. Lastly, GR may compete with NF-κB for nuclear coactivators, including CREB binding protein and p300, thereby reducing and inhibiting transcriptional activation by NF-κB. It should be noted that, in exerting its effect, activated GR did not affect the correct assembly of the pre-initiation (DAB) complex, but acted rather more proximally in inhibiting the correct assembly of transcription factors in the promoter region, and thus transcriptional initiation.