Glucocorticoid receptors are a type of nuclear receptor that are activated by the binding of cortisol (endogeneous glucocorticoid) resulting in shuttling from the cytoplasm to the nucleus and modulation of gene transcription (either activation or repression). Within the nucleus, activated glucocorticoid receptors bind to DNA via zinc fingers motifs in their DNA-binding domain. Glucocorticoids are administered in autoimmune disorders as well as cancer. Covalent selective glucocorticoid receptor agonists (SEGRA) of glucocorticoid receptors should only trigger repression of transcription and has applications in inflammatory diseases. Noncovalent SEGRA, GSK866, was modified by incorporating chloroacetamide or acrylamide warheads in a bid to obtain covalent agonists. The idea was to target cysteine residues in the vicinity of the ligand binding site, specifically Cys643. Covalent cysteine modification was confirmed by mass spectrometric analysis. While covalent SEGRAs are still in nascent stages, they show great potential in the treatment of inflammatory disorders. 284