Recent studies demonstrate that primary (hereditary) abnormalities in the glucocorticoid receptor gene make 6.6% of the normal population relatively ‘hypersensitive’ to glucocorticoids, while 2.3% are relatively ‘resistant’. These abnormalities might explain the well-known phenomenon that some individuals develop severe adverse effects during therapy with a low dose of glucocorticosteroids, while others do not develop side effects even during long-term therapy with a much higher dose. This heterogeneity in glucocorticoid sensitivity in the normal population might eventually allow the prediction of a ‘safe’ dose of glucocorticosteroids in individual patients. ‘Resistance’ to the beneficial clinical effects of glucocorticosteroid therapy in some patients with severe rheumatoid arthritis and asthma is probably seldom related to generalized primary (hereditary) glucocorticoid resistance. In most patients this ‘resistance’ seems to be acquired and localized to the inflammation sites, where it is caused by high local cytokine production which interferes with glucocorticoid action. Recognition of localized, acquired glucocorticoid resistance is of great importance, as alternative drug therapy with other immune-modulating drugs, such as cyclosporin and methotrexate, should be considered. Chronic high-dose glucocorticosteroid treatment in such patients insufficiently reduces symptomatology, while generalized side effects occur, as the rest of the body of the patient has a normal sensitivity to these drugs.