Synthetic glucocorticoids (GCs) are frequently used to treat various inflammatory and immune disorders. Unfortunately, long-term GC treatment is associated with many side effects. GCs bind to the glucocorticoid receptor (GR), an intracellular steroid receptor. Identifying improved GR ligands depends has been met with little success so far. Commonly used bio-assays do not fully capture the complex biology of how different GC ligands transmit signals within a cell. By an improved understanding, and quantitative monitoring of, GR activities at key nodes on the signaling pathway, better-informed predictions can be made that assist the development of GR-modulating ligands that are genuinely safer. Our project’s aim is to elucidate which changes in GR posttranslational modifications (PTMs), (novel) coregulator interactions and coregulator PTMs underly both clinical efficacy and side effects of GR across cell models. Hereto, we will map GR phospho-proteome, interactome, transcriptome and associated chromatin binding events in anti-inflammatory effector and side effect-related cell models, following treatment with functionally diverse ligands. We will integrate all information to gain a deep understanding of how ligand-class-specific signaling events link to a particular functional read-out. The insight can be of future use to develop unique bio-assays that have a higher predictive power to pinpoint GR activity per ligand class (antagonist, SEGRAM, partial agonist, full agonist).