Glucocorticoids (GCs) represent the most important and frequently used class of anti-inflammatory drugs. While the therapeutic effects of GCs have been known and used for more than 50 years, major progress in discovering the underlying molecular mechanisms has only been made in the last 10-15 years. There is consensus that the desired anti-inflammatory effects of GCs are mainly mediated via repression of gene transcription. In contrast, the underlying molecular mechanisms for GC-mediated side effects are complex, distinct, and frequently only partly understood. Recent data suggest that certain side effects are predominantly mediated via transactivation (e.g., diabetes, glaucoma), whereas others are predominantly mediated via transrepression (e.g., suppression of the hypothalamic-pituitary-adrenal axis). For a considerable number of side effects, the precise molecular mode is either so far unknown or both transactivation and transrepression seem to be involved (e.g., osteoporosis). The differential molecular regulation of the major anti-inflammatory actions of GCs and their side effects is the basis for the current drug-finding programs aimed at the development of dissociated GC receptor (GR) ligands. These ligands preferentially induce transrepression by the GR, but only reduced or no transactivation. This review summarizes the current knowledge of the most important GC-mediated side effects from a clinical to a molecular perspective. The focus on the molecular aspects should be helpful in predicting the potential advantages of selective GR agonists in comparison to classical GCs.