The biological mechanisms that determine cell-specific responses to glucocorticoid hormones may overlap with those that are associated with acquired glucocorticoid resistance. Cell and tIssue specificity can be brought about in many different ways. Studies on the brain, an important glucocorticoid target tIssue, may provide examples of regulatory mechanisms underlying response specificity at multiple levels. In this commentary a number of such mechanisms are discussed, with emphasis on regulation of glucocorticoid bio-availability by the efflux transporter P-glycoprotein and on the variable presence of nuclear proteins which modulate or interfere with gluco- and mineralocorticoid receptor-mediated transcription.