Glucocorticoids are four-ring steroid compounds that regulate a wide range of physiological systems ranging from embryonic respiratory development, immune function and responses to acute or chronic stress. Glucocorticoids are taken up by many target cells where they bind and activate cytoplasmic glucocorticoid receptors (GRs), which then dimerize, translocate to the nucleus and function as ligand-dependent transcriptional regulators. Synthetic glucocorticoids such as dexamethasone and prednisolone have for decades been the cornerstone for the clinical treatment of inflammatory diseases, such as rheumatoid arthritis and asthma, yet prolonged use have undesirable side-effects such as persistent immune suppression, metabolic imbalance, obesity, diabetes, and osteoporosis. Detailed understanding of the cell signaling mechanisms of GR action has led to the development of novel selective glucocorticoid receptor ligands that appear to offer more efficient treatments for a number of diseases while eliciting fewer side-effects. Additionally, in cell-based and animal model systems a number of compounds such as the methane sulphonamides and a novel compound A-348441 have shown promise as GR antagonists. Other classes of ligands such as the benzopyranoquinolines and the arylpyrazoles have further been shown to selectively influence the transcriptional regulatory properties of GRs on different target gene in various cellular contexts. These selective GR modulators are believed to initiate transcriptional co-regulator recruitment that in turn promotes specific gene responses relevant to the more efficient and specific treatment of inflammatory conditions and metabolic diseases such as type-2 diabetes.