Resistance to the anti-inflammatory effects of glucocorticoids in asthma and other inflammatory and immune diseases is uncommon, but presents a management problem. Understanding the mechanisms of steroid resistance provides new insights into the mechanism of steroid action as well as the underlying chronic disease process. In patients with primary steroid-resistant (SR) asthma there is no abnormality in the pharmacokinetics of the exogenous steroid and no significant defect in steroid binding to the glucocorticoid receptor (GR). Recent studies have demonstrated a marked reduction in the binding of GR to DNA; this appears to be due to increased binding of GR to the transcription factor activator protein-1 (AP-1). Secondary steroid resistance in asthma may arise in response to the release of cytokines that activate AP-1 and other transcription factors that bind directly to GR. A similar effect may also be seen with high concentrations of beta 2-agonists that activate another GR binding transcription factor, CREB. Several existing and novel treatment strategies are possible in the management of SR asthma.