Glucocorticoid receptor agonists are most potent anti-inflammatory agents and indispensable for the treatment of a broad array of inflammatory and immunological disorders. The first compounds introduced into therapy were derived from the natural corticosteroid hydrocortisone. First structural modifications of the core molecule aimed at the increase in selectivity to the glucocorticoid over the mineralocorticoid receptor. Based on a better understanding of structure-activity relationships the next generation of compounds displayed higher receptor affinities and thus higher efficacy. For topically applied glucocorticoids, further progress was achieved by drug targeting, e.g. by inhalation of corticosteroid preparations. Recent developments focussed on the best possible reduction of adverse effects by introducing metabolically labile functional groups into the active molecule to minimize systemic exposure. High affinity to the therapeutic target tissue was recognized as a property that warrants a favorable redistribution kinetics into systemic circulation. These concepts led to a significant improvement of the therapeutic index defined as the ratio of undesired metabolic effects to beneficial antiinflammatory activity for topically applied glucocorticoids. In contrast, no comparable progress has been achieved for systemically administered glucocorticoids yet. However, new insights into alternate pathways of receptor activation suggest the potential for an agonist-driven differentiation between transactivation and transrepression mechanisms. This molecular effector selectivity gives rise to the hope for the development of compounds exhibiting predominantly therapeutically desired effects. This review discusses structure-property relationships of orally and inhalative administered glucocorticoid receptor ligands with steroidal and non-steroidal structure and their translations into clinically observed efficacy and adverse effects.