Glucocorticoid action in cells is mediated by a specific receptor protein, the glucocorticoid receptor (GR). GR is a member of a superfamily of ligand-inducible transcription factors that control a variety of physiological functions; such as, metabolism, development, and reproduction. Unliganded GR is predominantly localized within the cytoplasm but rapidly and efficiently translocates to the nucleus following hormone binding. This review will focus on the intracellular signaling pathway utilized by the GR including the mechanisms that control its intracellular trafficking, hormone binding and transcriptional regulation. Many receptor-interacting proteins are involved in distinct steps in GR signal transduction, each with a unique mechanism to regulate receptor action and providing potential drug targets for the manipulation of cellular responses to glucocorticoids.