Glucocorticoids are the mainstay of asthma management and effectively treat acute exacerbations of asthma. However, a small subset of asthmatics, usually with severe asthma, respond poorly even to systemic administration of high-dose glucocorticoids and this condition is termed "steroid-resistant asthma". This cohort, although small, accounts for approximately 50% of total health care cost for asthma. New investigations into the mechanisms of glucocorticoid action have broadened and deepened our understanding of glucocorticoid resistance. Here we review the importance and characteristics of steroid resistant asthma, the mechanisms that mediate the function of glucocorticoids and that lead to the development of this disease and potential therapies to reverse resistance to treatment. Cellular and molecular factors, receptors and complex signalling pathways have all been implicated. Indeed, based on molecular biological studies, excessive activation of intracellular transcription factors, impaired histone deacetylase, and epigenetic (such as miR-18 and miR-124a) as well as other factors (e.g. vitamin D, P-glycoprotein 170, and macrophage migration inhibitory factor and T helper 17 cells and factors related to innate immunity (such as IFN-gamma and LPS)) may result in glucocorticoid resistance. A thorough understanding of the pathogenesis of steroid resistant asthma will help to develop more efficacious agents for the treatment of the disease.