<p>Glucocorticoid receptor (GR) is a member of the nuclear hormone receptor family, which acts as a transcription factor when bound by glucocorticoid (GC) ligands. GR is expressed in nearly all tissue types and regulates essential processes such as inflammation, immune regulation and metabolism. Given its ubiquitous role, GR has frequently been associated with a wide range of illnesses, particularly in the fields of allergy, pulmonary, dermatology, rheumatology, or ophthalmology. It was reported that GCs either contribute to their development or serve as part of their treatment, making them the most prescribed drugs worldwide. GR activity and signaling is finely regulated by a network of post-translational modifications (PTMs). Indeed, PTMs can alter GR behavior and function by modifying its localization, stability, interaction with other proteins and transcriptional activity. Aside from the well-characterized phosphorylation events, additional PTMs are implicated in GR activity and their dysregulation has been described in various diseases. This review provides an integrated overview of current knowledge on GR PTMs, highlighting both mechanistic insights and their relevance in disease. We will present how aberrant PTMs contribute to extremely prevalent diseases, such as cancer, chronic inflammatory diseases, Alzheimer’s disease and other neurological diseases. Special attention will be given to the specific readers of these PTMs and to the enzymes catalyzing these modifications, as they represent promising therapeutic targets.</p>