Steroid insensitivity in severe asthma is rare but has huge health care costs. Thus, 5% of asthmatic patients account for approximately 50% of total health care costs. Incorrect diagnosis, non-compliance with therapy and psychological problems are all confounding issues, and can account for a failure to respond to steroids in many of these patients. A recent report (ENFUMOSA) has suggested that severe asthma, of which steroid-resistant asthma is a component, consists of at least one, possibly more, distinct disease(s) with differing pathologies. Future studies such as Bio-Air and TENOR could confirm this; therefore, it is not surprising that well-characterised steroid-resistant and steroid-dependent asthma have multiple mechanisms to account for a lack of steroid sensitivity, including defective ligand binding to the steroid receptor, abnormal receptor nuclear translocation and abnormal association with pro-inflammatory nuclear proteins. Distinct treatments might have to be tailored to the individual patient; for example, drugs that enhance receptor nuclear translocation will only be effective in patients in whom this is a problem. Once issues of diagnosis, compliance and psychological disorders have been resolved, true steroid resistance or dependence is unlikely to be an issue for most clinicians, who will rarely, if ever, see these patients. However, management of those few patients with true steroid resistance will require novel therapies tailored to specific subgroups of patients.