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▸ Glucocorticoid insensitivity is a considerable problem in respiratory disease. ▸ Insensitivity to steroids is due to a wide variety of exogenous and endogenous factors. ▸ We review recent advances in understanding the underlying molecular mechanisms. ▸ Glucocorticoid responsiveness can be restored in experimental models.Glucocorticoids (corticosteroids) are effective and clinically useful medicines for repressing inflammation in lung disease; however, the number of respiratory conditions that have been recognized to be refractory or insensitive to glucocorticoids is on the rise — either due to an inherent difference in the glucocorticoid sensitivity as part of the disease process or due to exogenous stressors such as cigarette smoke and other oxidative insults. Independent of causality, the aim of future therapeutic advances to conquer this frontier will no doubt be based on our growing knowledge of molecular mechanisms underlying glucocorticoid insensitivity in respiratory diseases. The current article aims to highlight the key molecular mechanisms responsible for glucocorticoid insensitivity in asthma and COPD. This new knowledge will ultimately allow us to enhance lung health by restoring glucocorticoid responsiveness in respiratory disease. In this way, our increased understanding of corticosteroid insensitivity can be exploited as a source of drug targets for respiratory disease in the future.