Glucocorticoids (GC) such as cortisol regulate multiple physiological functions, 
notably those involved in development, metabolism, inflammatory processes and 
stress, and exert their effects upon binding to the glucocorticoid receptor (GR, 
encoded by NR3C1 gene in humans). GC signaling follows several consecutive steps 
leading to target gene transactivation, including ligand binding, nuclear 
translocation of ligand-activated GR complexes, DNA binding, and recruitment of 
functional transcriptional machinery. Generalized glucocorticoid resistance 
syndrome, due to GR loss-of-function mutations, may be related to the impairment 
of one of the GC signaling steps. To date, 31 NR3C1 loss-of-function mutations 
have been reported in patients presenting with various clinical signs such as 
hypertension, adrenal hyperplasia, hirsutism or metabolic disorders associated 
with biological hypercortisolism but without Cushing syndrome signs and no 
negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. 
Functional characterization of GR loss-of-function mutations often demonstrates 
GR haploinsufficiency and a decrease of GR target gene induction in relevant 
cell types. The main signs at presentation are very variable from resistant 
hypertension, bilateral adrenal hyperplasia likely related to increased ACTH 
levels but not exclusively, hirsutism to isolated renin-angiotensin-aldosterone 
system abnormalities in a context of 11βHSD2 deficiency. Some mutated GR 
patients are obese or overweight together with a healthier metabolic profile 
that remains to be further explored in future studies. Deciphering the molecular 
mechanisms altered by GR mutations should enhance our knowledge on GR signaling 
and ultimately facilitate management of GC-resistant patients. This review also 
focuses on the criteria facilitating identification of novel NR3C1 mutations in 
selected patients.