As a powerful anti-inflammatory, immunosuppressive, and antiproliferative drug, glucocorticoid (GC) plays an important role in the treatment of various diseases. However, some patients may experience glucocorticoid resistance (GCR) in clinical, and its molecular mechanism have not been determined.The authors performed a review of the literature on GCR focusing on mutations in the NR3C1 gene and impaired glucocorticoid receptor (GR) signalling, using METSTR (2000 through May 2022) to identify original articles and reviews on this topic. The search terms included 'glucocorticoid resistance/insensitive', 'steroid resistance/insensitive', 'NR3C1', and 'glucocorticoid receptor'.Primary GCR is mainly caused by NR3C1 gene mutation, and 31 NR3C1 gene mutations have been reported so far. Secondary GCR is caused by impaired GC signalling pathways, including decreased expression of GR, impaired nuclear translocation of GR, and impaired binding of GR to GC and GR to target genes. However, the current research is more on the expression level of GR, and there are relatively few studies on other mechanisms. In addition, methods for improving GC sensitivity are rarely reported.The molecular mechanisms of GCR are complex and may differ in different diseases or different patients. In future studies, when exploring the mechanism of GCR, methods to improve GC sensitivity should also be investigated.© 2022 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.