Abstract: The development of glucocorticoid (GC) resistance is a serious problem that complicates the treatment of immune-related diseases, such as asthma, ulcerative colitis, and hematologic cancers. hGRα and hGRβ are two isoforms of the human glucocorticoid receptor, which differ in the structural composition of the carboxy-terminal end of the ligand-binding domain and therefore in their ability to bind glucocorticoid ligand and in their physiological function. hGRα is the classically functional GR, while hGRβ seems to act mainly as a dominant negative to the function of hGRα. Because of the ability of hGRβ to antagonize the action of hGRα, it has been hypothesized that changes in the expression of hGRβ may underlie the development of glucocorticoid resistance. In this article we review what is known about the expression and physiological action of hGRβ in normal cells and tissue as well as in several disease states. Taken together, the evidence suggests that the ratio of hGRα:hGRβ expression is indeed critical to the glucocorticoid responsiveness of various cells. This ratio can be altered by changing the expression level of hGRα, hGRβ, or both receptors simultaneously. Higher ratios correlate with glucocorticoid sensitivity, while lower ratios correlate with glucocorticoid resistance. Thus hGRβ can be an important modulator of glucocorticoid responsiveness.