After binding to an activating ligand, such as corticosteroid, the glucocorticoid receptor (GR) performs an impressive array of functions ranging from nuclear translocation, oligomerization, cofactor/kinase/transcription factor association, and DNA binding. One of the central functions of the receptor is to regulate gene expression, an activity triggered by ligand binding. In this role, GR acts as an adapter molecule by encoding the ligand's message within the structural flexibility of the ligand binding domain (LBD). The purpose of this review is to discuss the many structural and functional features of the GR LBD in light of recent successful biochemical and crystallographic studies. Progress in this area of research promises to reveal new strategies and insights allowing for the design of novel drugs to treat inflammatory diseases, diabetic conditions, steroid resistance, and cancers.