Synthetic glucocorticoids are among the most effective anti-inflammatory drugs available. The activity of this drug class is mediated by the glucocorticoid receptor, a nuclear steroid receptor whose endogenous ligand is the adrenal hormone cortisol. Chronic glucocorticoid treatment is accompanied by serious side-effects, reflecting the symptoms of cortisol excess seen in Cushings syndrome patients. During the past 50 years advances to this drug class have been limited largely to reducing systemic exposure through inhaled delivery and increasing glucocorticoid receptor selectivity. However, a safer oral drug for the treatment of conditions such as rheumatoid arthritis, inflammatory bowel disease, and transplant rejection, still represents a major unmet medical need. Over the past 20 years, mechanisms of glucocorticoid receptor action have been elucidated. Before the gene was even cloned, the glucocorticoid receptor was known to be a ligand-induced DNA binding protein. Identification of hormone response elements in the promoters of metabolic target genes in the liver provided a model for its broad activities. It was since revealed that much of its anti-inflammatory activity is not DNAdependent after all, but instead is the result of a complex set of protein-protein interactions which lead to transcriptional inhibition of pro-inflammatory targets. Thus, a glucocorticoid receptor ligand that dissociates the DNA binding and protein interaction mediated activities is expected to show improved safety. This review will focus on the scientific advances, which impact the development of this hypothesis and will present a survey of current preclinical drug candidates employing this strategy.