In a recent issue of CHEST (August 2008), Adcock and Barnes1 presented a very interesting and informative study on the molecular mechanism of glucocorticoid (GC) resistance. As the author stated, understanding in detail the action, and inaction, of GCs may lead to the development of new antiinflammatory drugs that are able to subvert the relative corticosteroid insensitivity that is characteristic of patients with severe asthma and COPD. We want to call attention to the prereceptor metabolism of GCs, another mechanism that may have a role in GC resistance. Within target tissues, cortisol and its inactive metabolite, cortisone, are interconverted through the activity of 11β-hydroxysteroid dehydrogenase (11β-HSD).2 Two 11β-HSD isoforms have been characterized and are expressed in lung tissue and immunity cells. In particular, 11β-HSD1 acts as a ketoreductase by virtue of the intracellular localization within the lumen of the endoplasmic reticulum in proximity to the hexose-phosphate dehydrogenase (H6PD).3 H6PD couples the oxidation of hexose-6-phosphate to the reduction of nicotinamide adenine dinucleotide phosphate (NADPH). It is the generation of NADPH within the endoplasmic reticulum adjacent to 11β-HSD1 that drives its reaction direction. Intracellular GC regeneration by 11β-HSD1 is dependent not just on its steroid substrate, but also on G6P import into the endoplasmic reticulum and H6PD-mediated production of NADPH.