Corticosteroids are the most effective treatment for asthma but the therapeutic response varies markedly between individuals. Multiple factors including genetic, environmental, asthma related and concordance are likely to contribute to the heterogeneous response to corticosteroids. Genetic variations at the level of the glucocorticoid receptor have not been implicated to date, but polymorphisms of TBX21 and corticotrophin-releasing hormone receptor 1 genes are associated with enhanced efficacy to inhaled corticosteroids. Cigarette smoking is an important cause of insensitivity to corticosteroids. Mechanisms of corticosteroid insensitivity in smokers with asthma are currently unexplained, but could be due to alterations in airway inflammatory cell phenotypes, changes in glucocorticoid receptor α to β ratio, and/or reduced histone deacetylase activity. Exposure to allergens, infections and neutrophilic airway inflammation as well as race and the rare phenotype of corticosteroid resistant asthma are implicated in reduced efficacy. Poor concordance with treatment is of particular importance. Management involves advice on smoking cessation for smokers, assessment of concordance and inhaler technique, review of delivery of care and step up in treatment only after these issues have been addressed. In the future, corticosteroid treatment might be guided by pharmacogenetic assays and the use of alternative or additional drugs for specific corticosteroid insensitive groups such as smokers with asthma.