In recent years, increased awareness and availability of proper diagnostic tools have made subclinical endocrine disease an emerging issue. The clinical impact of subtle alterations of hormonal secretion and/or action depends on the sensitivity of target cells, which shows wide interindividual variability, and within the same individual, varies among tissues and changes in particular microenvironments, eg when inflammation is present. Subclinical hypercortisolism is a typical example of this new approach which privileges hormonal action rather than secretion. In the present paper, we concisely review the mechanisms of genomic and non-genomic actions of glucocorticoids (GC), and the determinants of GC sensitivity, with special attention to those more investigated in relation to bone metabolism: GC receptor (GR) types, isoforms and polymorphisms, and 11beta-hydroxysteroid dehydrogenase (11beta-HSD) shuttle. Detailed knowledge of the mechanisms of GR action has opened the way to the development of novel selective GR modulators or selective GR agonists, which show promise of being efficacious for specific treatments of disease having fewer side effects. Exogenous GC excess due to the therapeutic use of GC is the most frequent cause of secondary osteoporosis. Variability of therapeutic or detrimental effects among patients and in the same patient as a function of the clinical course is nowadays recognized to depend on numerous factors. While intermediate to high doses are likely to overcome inter-individual differences in sensitivity, assessment of clinical efficacy and monitoring of adverse effects are of special importance for chronic users of low-dose GC; in these patients prediction of individual response seems still far from clinical practice. In the next future evaluation of GR polymorphisms and 11beta-HSD activities are likely to become important components of a comprehensive approach aimed to" tailor" the therapeutic strategy to the individual risk/benefit ratio.