Glucocorticoids (GCs) are potent immune suppressive drugs with unfortunately severe side effects. Different molecular modes of actions of the GC receptor (GR) have been identified. Transcriptional transactivation by binding of a dimerized GR protein complex to the promoter of GC regulated genes or interference with activity of pro-inflammatory transcription factors by GR monomers are considered as the two major mechanisms. It has been hypothesized that selective GR agonists (SEGRAs) addressing dimer-independent function would reveal potent steroid therapeutic activity with reduced side effects. Recent studies of a mouse knock-in strain with a dimerization-deficient GR demonstrate that some inflammatory processes can be suppressed by GCs, while others cannot. Also side effects of GCs occur in these mice. Thus, depending on the process that is treated, SEGRA could be therapeutically more or less effective and not all side effects of steroid therapy may be reduced.