At the present time, emphasis is placed on viewing asthma as a manifestation of chronic airway inflammation, possibly secondary to allergen hypersensitivity. Consequently, one aspect of management is to institute measures of environmental control to minimize the inflammatory response related to allergen stimulation, and to administer anti-inflammatory therapy to resolve inflammation and prevent progression of disease. Most patients respond very favourably to conventional therapy, as recommended in recent guidelines for asthma management. Some cases, however, remain very difficult to control despite high-dose inhaled glucocorticoids, even combined with oral glucocorticoid therapy. Management of these patients raises questions about the conditions that alter response to glucocorticoid therapy. The patient with difficult to control asthma not only presents a challenge to clinical management but raises new questions concerning our ability to control the progression of disease. Is difficult to control asthma secondary to overwhelming or ongoing allergen exposure? Do anti-inflammatory medications, specifically inhaled glucocorticoids, really control the progression of the disease? Are these patients destined to become severe asthmatics at birth due to the inherent characteristics of their airways, or is this indeed a consequence of progressive inflammation? This review will summarize present concepts of glucocorticoid-resistant asthma, current knowledge of the mechanisms of persistent inflammation, and the implications for management. The gaps in information will also be addressed in order to stimulate interest in further research that could lead to better understanding of the disease and potential windows for therapeutic intervention.