Recent insights into the mechanisms of genomic and non-genomic glucocorticoid actions have stimulated the search for novel glucocorticoid receptor ligands. These efforts are driven by the need to improve the benefit-risk ratio of these important drugs. Glucocorticoids are very frequently and successfully used drugs which mediate important immunosuppressive and anti-inflammatory effects, but unfortunately they have pleiotropic effects causing a number of adverse reactions which limit their clinical use, especially at higher dosages and for longer periods. For this reason, novel glucocorticoid receptor ligands are being developed, among them selective glucocorticoid receptor agonists (SEGRAs). SEGRAs are drugs that predominantly induce transrepression effects (inhibition of protein synthesis), whereas the transactivation activity (induction of protein synthesis) is significantly reduced as compared with conventional glucocorticoid drugs. This makes sense since it became evident over the last few years that many adverse effects are predominantly caused by the transactivation mechanism, whereas anti-inflammatory effects are mostly mediated by transrepression mechanisms. Other interesting examples for exciting new developments are NO-glucocorticoids and long-circulating liposomal glucocorticoids. It is, however, true of all these developments that further in vivo and in vitro investigations and clinical trials will have to define in more detail their safety-efficacy profile in order to answer the questions whether these drugs as "improved glucocorticoids" will enter clinical medicine in the near future.