Taking into consideration that glucocorticoid (GC) hormones have been used clinically for over half a century and that more than 20 yr have passed since the cloning of the GC receptor (GR), it is hard to imagine that novel aspects in the molecular mechanism by which GCs mediate their antiinflammatory actions are still being unveiled today. Partly, this is because almost on a daily basis, novel insights arise from parallel fields, e.g. nuclear receptor cofactor and chromatin regulation and their concomitant impact on gene transcription events, eventually leading to a revisitation or refinement of old hypotheses. On the other hand, it does remain striking and puzzling why GCs use different mechanisms in so many different cell types and on many different target genes to elicit an antiinflammatory effect. Meanwhile, the obvious question for the clinic remains: is the separation of GR functionalities through differential ligand design the strategy of choice to avoid most GC-mediated side effects? This minireview aims to highlight some of the latest findings on aspects of the antiinflammatory working mechanisms of GCs.