Glucocorticoids, the main anti-inflammatory medication, are useful for the treatment of many diseases such as inflammation, respiratory diseases, malignancies, etc., but unfortunately, glucocorticoids cannot inhibit inflammation by various mechanisms. The definition of glucocorticoid resistance is loss of efficacy or reduced sensitization over time and increases due to chronic inflammation. It is affecting 30% of glucocorticoid-treated patients. It shows an essential restriction in the treatment of chronic inflammation and malignancies diseases and can be due to the impairment of various mechanisms along the signaling pathway of glucocorticoids. However, glucocorticoids dissociation has been improved to reduce the SE, DIGRAs “receptor of glucocorticoid dissociation agonists” are a group of trial drugs developed to share various wanted as an anti-inflammatory, suppress immunity, or properties of anti-malignancies of traditional steroids medications with lesser adverse events, but it is so hard to dissociate anti-inflammatory effects from adverse effects. Cases with glucocorticoid unresponsive should use other medications with similar mechanisms in inflammation as well as drugs that may change the molecular mechanism of resistance to glucocorticoid. Here, we discuss the evidence that exists for the hypothesis that individual glucocorticoid resistance underlies the problem.