There is a considerable and growing unmet medical need in respiratory disease concerning effective anti-inflammatory therapies for conditions such as severe asthma, chronic obstructive pulmonary disease and cystic fibrosis. These diseases share a predominant characteristic of an enhanced and uncontrolled inflammatory response in the lungs, which contributes to disease progression, hospitalization and mortality. These diseases are poorly controlled by current anti-inflammatory therapies including glucocorticoids, which are otherwise effective in many other inflammatory conditions or in milder disease such as asthma. The exact cause of this apparent impairment of glucocorticoid function remains largely unclear; however, recent studies have now implicated a number of possible mechanisms. Central among these is an elevation of the oxidant burden in the lungs and the resulting reduction in the activity of histone deacetylase (HDAC)-2. This contributes to both the enhancement of proinflammatory mediator expression and the impaired ability of the glucocorticoid receptor (GR)-alpha to repress proinflammatory gene expression. The oxidant-mediated reduction in HDAC-2 activity is, in part, a result of an elevation in the phosphoinositol 3-kinase (PI3K) delta/Akt signalling pathway. Blockade of the PI3Kdelta pathway restores glucocortiocoid function in both in vitro and in vivo models, and in primary cells from disease. In addition, inhibition of the PI3Kdelta and PI3Kgamma isoforms is anti-inflammatory in both innate and adaptive immune responses. Consequently, selective inhibition of this pathway may provide a therapeutic strategy both as a novel anti-inflammatory and in combination therapy with glucocorticoids to restore their function. However, a number of other oxidant-related and -unrelated mechanisms, including altered kinase signalling and expression of the dominant negative GRbeta, may also play a role in the development of glucocorticoid insensitivity. Further elucidation of these mechanisms and pathways will enable novel therapeutic targeting for alternative anti-inflammatory drugs or combination therapies providing restoration for the anti-inflammatory action of glucocorticoids.