The term "steroid-resistant (SR) asthma" has been used to describe a group of asthmatics who demonstrate persistent airway obstruction and inflammation despite treatment with high doses of systemic glucocorticoids. There are at least two forms of SR asthma, that is, primary and acquired types. Type I SR asthma is acquired and is associated with abnormally reduced glucocorticoid receptor (GR) ligand and DNA binding affinity. Type II SR asthma is due to a primary GR binding abnormality. An important distinction between these two types of SR asthma is that the GR defect in Type I, but not Type II, SR asthma is reversible in culture and is sustained by incubation with combination IL-2 and IL-4. The treatment of these patients requires a systematic approach to rule out confounding factors, including triggers of immune activation, optimizing steroid therapy, and use of alternative strategies to inhibit airway inflammation.