Glucocorticoids have a broad array of life-sustaining functions and play an important role in the therapy of many diseases. Thus, changes of tissue sensitivity to glucocorticoids may be associated with and influence the course and treatment of many pathologic states. Such tissue sensitivity changes may present on either side of an optimal range, respectively as glucocorticoid resistance or hypersensitivity, and may be generalized or tissue-specific. Familial/sporadic glucocorticoid resistance syndrome caused by inactivating mutations of the glucocorticoid receptor (GR) gene is a classic monogenic disorder associated with congenital, generalized glucocorticoid insensitivity, while several autoimmune, inflammatory and allergic diseases are often associated with resistance of the inflamed tissues to glucocorticoids. On the other hand, glucocorticoid hypersensitivity has been suggested in visceral obesity-related insulin resistance associated with components of the metabolic syndrome, and in the acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus type-1 (HIV-1) infection. Here, we have reviewed the molecular analyses of five familial and three sporadic cases of the familial/sporadic glucocorticoid resistance syndrome and discussed the possible contribution of newly identified molecules, such as HIV-1 accessory proteins Vpr and Tat, FLICE-associated huge protein (FLASH) and chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), on the molecular regulation of GR activity, as well as their possible contribution to changes in tissue sensitivity to glucocorticoids in pathologic conditions.