Glucocorticoids are strong anti-inflammatory drugs used to treat a large number of diseases but are linked to severe side effects. The glucocorticoid receptor (GR) is a transcription factor and the side-effects are mostly linked to activation of metabolic GR target genes by GR dimers or oligomers. The anti-inflammatory effects are mediated by repression of pro-inflammatory transcription factors by the activated GR. Selective GR Activators or Modulators (SEGRAMs) are GR ligands with intact repression but reduced GR target gene activation. SEGRAMs are anti-inflammatory but have fewer side effects. How the GR oligomerizes is poorly defined and it is unclear why the different GR ligands have a different balance between activation and repression. In this project, we generate thousands of GR mutants and test them in combination with different GR ligands in different relevant gene activation and repression assays. We model the effect of the mutants on the GR structure and study the effects of interesting mutants on GR oligomerization, GR-protein interactions, and GR anti-inflammatory functions. This will reveal in detail how GR ligands obtain their specific gene activation/repression profile and can lead to the development of better GR ligands without side effects.