Background: Corticosteroids are the most potent anti-inflammatory agents for the treatment of mild to moderate asthma. However, a small percentage of the asthma population (< 10%) do not respond well, or at all, to corticosteroid therapy, and this severe corticosteroid-refractory asthma contributes to more than 50% of health care expenditure for all asthma because these is no appropriate pharmacological therapy. Methods: If the molecular mechanism of corticosteroid insensitivity is uncovered, it may in turn provide insights into the key mechanism of corticosteroid action and rational implementation of treatment regimens that restore corticosteroid sensitivity or replace corticosteroid therapy. This review focuses on why severe asthma patients are corticosteroid-insensitive, and discusses present and future therapeutic and preventative strategies for corticosteroid-refractory asthma. Conclusions: Corticosteroid-refractory asthma is a heterogeneous disease and can be controlled by add-on treatment of corticosteroid-sparing agents or effective new drugs based on individual abnormalities. The elucidation of the cause of the relative lack of corticosteroid response in this subgroup of asthmatic individuals may have important implications for other diseases.