B-hydroxysteroid dehydrogenases (11b-HSDs) catalyze the in- terconversion of active glucocorticoids (cortisol, corticosterone) and inert 11-keto forms (cortisone, 11-dehydrocorticosterone). 11b-HSD type 2 has a well recognized function as a potent dehydrogenase that rapidly inactivates glucocorticoids, thus allowing aldosterone selec- tive access to otherwise nonselective mineralocorticoid receptors in the distal nephron. In contrast, the function of 11b-HSD type 1 has, until recently, been little understood. 11b-HSD1 is an ostensibly reversible oxidoreductase in vitro, which is expressed in liver, adipose tissue, brain, lung, and other glucocorticoid target tissues. However, increasing data suggest that 11b-HSD1 acts as a predominant 11b- reductase in many intact cells, whole organs, and in vivo. This reac- tion direction locally regenerates active glucocorticoids within ex- pressing cells, exploiting the substantial circulating levels of inert 11-keto steroids. While the biochemical determinants of the reaction direction are not fully understood, insights to its biological importance have been afforded by use of inhibitors in vivo, including in humans, and the generation of knockout mice. Such studies suggest 11b-HSD1 effectively amplifies glucocorticoid action at least in the liver, adipose tissue, and the brain. Inhibition of 11b-HSD1 represents a potential target for therapy of disorders that might be ameliorated by local reduction of glucocorticoid action, including type 2 diabetes, obesity, and age-related cognitive dysfunction. (Endocrinology 142: 1371- 1376, 2001)