Although the majority of patients with asthma respond favorably to inhaled and systemic glucocorticoids, up to 25% of patients with difficult-to-control asthma have poor clinical responses to high doses of systemic glucocorticoids. Early identification of these patients is required to minimize serious side effects from long-term systemic glucocorticoid therapy in patients who are insensitive to such therapy. Recent studies indicate that these individuals have developed diminished glucocorticoid receptor ligand and DNA binding affinity as the result of poorly controlled immune activation potentially triggered by allergens or infection. The current review will examine the immune mechanisms underlying glucocorticoid resistance and discuss the management of this challenging group of patients.