Glucocorticoids are among the most successful therapies in the treatment of chronic inflammatory and autoimmune diseases. Their efficacy seems to be caused by the interference of the ligand-activated glucocorticoid receptor with many pro-inflammatory pathways via different mechanisms. The ubiquitous expression of the glucocorticoid receptor is a prerequisite for efficacy. Their main drawback, however, is due to their potential to induce adverse effects, in particular upon high dosage and prolonged usage. For the purpose reducing systemic side effects, topical glucocorticoids that act locally have been developed. Nevertheless, undesirable cutaneous effects such as skin atrophy persist from the use of topical glucocorticoids. Therefore a high medical need exists for drugs as effective as glucocorticoids but with a reduced side effect profile. Glucocorticoids function by binding to and activating the glucocorticoid receptor which positively or negatively regulates the expression of specific genes. Several experiments suggest that negative regulation of gene expression by the glucocorticoid receptor accounts for its anti-inflammatory action. This occurs through direct or indirect binding of the receptor to pro-inflammatory transcription factors that are already bound to their regulatory sites. The positive action of the receptor occurs through homodimer binding of the ligand receptor complex to discrete nucleotide sequences and this contributes to some of the adverse effects of the hormone. Glucocorticoid receptor ligands that promote the negative regulatory action of the receptor with reduced positive regulatory function should therefore show an improved therapeutic index. A complete separation of the positive from the negative regulatory activities of the receptor has so far not been possible because of the interdependent nature of the two regulatory processes. Nevertheless, recent understanding of the molecular mechanisms of the GR has triggered several drug discovery programs and these have led to the identification of dissociated GR-ligands. Such selective GR agonists (SEGRAs) are likely to enter clinical testing soon.