Glucocorticoids (GCs) are the most common group of medications used in the treatment of allergic and autoimmune disorders. They produce potent anti-inflammatory effects by inducing or repressing the expression of target genes. Although most patients with allergic diseases and autoimmune disorders respond to GC therapy, a small subset of patients demonstrate persistent tissue inflammation despite treatment with high doses of GCs. This condition results from an interaction between susceptibility genes, the host's environment, and immunologic factors. The treatment of these patients requires a systematic approach to rule out underlying conditions that lead to steroid resistance or treatment failure, as well as the use of alternative strategies to inhibit tissue inflammation.