The action of cortisol depends on its level in the circulation and its metabolism in tissues. Abnormal tissue cortisol metabolism has been implicated in hypertension, diabetes, osteoporosis and inflammatory arthritis. Local cortisol metabolism can involve conversion of cortisol to less active glucocorticoids or the local generation of cortisol from inactive cortisone. From a potential clinical/translational perspective most attention has focussed on the 11beta-hydroxysteroid dehydrogenases (11b-HSDs) which interconvert cortisone and cortisol. 11b-HSD1 is an activating enzyme generating cortisol from cortisone whereas 11b-HSD2 inactivates cortisol to cortisone. In vitro and ex vivo studies has characterised expression of these enzymes in various tissues. However, the functional consequences of enzyme activity in specific tissues or disease states in vivo have been harder to study, particularly in humans. Commonly employed techniques to measure enzyme activity in vivo have included measurement of cortisol and cortisone in biological fluids and cortisol metabolite ratios in urine collections. Isotopic methods have been developed that provide information about the extent of steroid interconversion across a vascular bed. The assessment of functional consequences of enzyme activity is still heavily dependent on the study of monogenic human disorders, the effects of enzyme inhibitors and transgenic technology. This presentation will focus on some of the approaches that have been employed to examine the clinical/translational importance of local cortisol metabolism in general and more specifically in osteoporosis and rheumatoid arthritis.