Glucocorticoids play a fundamental role in many physiologic functions and contribute substantially to the achievement of homeostasis. These pleiotropic glucocorticoid actions are mediated by a ubiquitously expressed transcription factor, the human glucocorticoid receptor (hGR), which may influence the transcription rate of numerous target genes, interact with other transcription factors, trigger the activation of several kinase pathways or modulate mitochondrial DNA expression. Any genetic defects in the NR3C1gene that encodes the hGR may cause Primary Generalized Glucocorticoid Resistance or Hypersensitivity Syndromes, two rare allostatic endocrinologic conditions characterized by partial impaired tissue sensitivity to glucocorticoids. However, there are patients who present with clinical manifestations suggestive of the above syndromes and do not harbor an inactivating or activating point mutation, insertion or deletion in the NR3C1gene. In these cases, several other factors might influence the glucocorticoid signal transduction. In this review, we discuss the numerous glucocorticoid functions and the multiple hGR isoforms, we present the genomic, nongenomic and mitochondrial glucocorticoid signaling cascade and we summarize the clinical manifestations and pathogenesis of Primary Generalized Glucocorticoid Resistance or Hypersensitivity Syndromes. Finally, we speculate that the next generation sequencing technologies will undoubtedly enable us to gain a deeper understanding of the GR “interactome”.