Glucocorticoids (GCs) are hormones naturally released when the body perceives stress and function to return homeostatic balance within various tissues. Synthetic GCs are widely prescribed therapeutics for the treatment of numerous inflammatory disorders and cancers. The effects of GCs are mediated by their binding and activation of the GC receptor (GR), a transcription factor that is subject to hormone-dependent and -independent phosphorylation on several serine and threonine residues. The GR is phosphorylated by kinases such as MAPKs, CDKs, and GSK-3beta, and these modifications modulate the transcriptional activity of the GR within cells. Here, we discuss the phosphorylation status of the GR as a mechanism to dictate how cells will ultimately respond to GCs. In doing so, we will review current knowledge about each phosphorylated residue within the GR and their contributions to modulating GC signaling in normal homeostatic physiology and during the progression of disease.