Glucocorticoids exert their extremely diverse effects on numerous biologic activities of humans via only one protein module, the glucocorticoid receptor (GR). The GR binds to the glucocorticoid response elements located in the promoter region of target genes and regulates their transcriptional activity. In addition, GR associates with other transcription factors through direct protein-protein interactions and mutually represses or stimulates each other's transcriptional activities. The latter activity of GR may be more important than the former one, granted that mice harboring a mutant GR, which is active in terms of protein-protein interactions but inactive in terms of transactivation via DNA, survive and procreate, in contrast to mice with a deletion of the entire GR gene that die immediately after birth. We recently found that GR physically interacts with the chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), which plays a critical role in the metabolism of glucose, cholesterol, and xenobiotics, as well as in the development of the central nervous system in fetus. GR stimulates COUP-TFII-induced transactivation by attracting cofactors via its activation function-1, while COUP-TFII represses the GR-governed transcriptional activity by tethering corepressors, such as the silencing mediator for retinoid and thyroid hormone receptors (SMRT) and the nuclear receptor corepressors (NCoRs) via its C-terminal domain. Their mutual interaction may play an important role in gluconeogenesis, lipoprotein metabolism, and enzymatic clearance of clinically important compounds and bioactive chemicals, by regulating their rate-limiting enzymes and molecules, including the phosphoenolpyruvate carboxykinase (PEPCK), the cytochrome P450 CYP3A and CYP7A, and several apolipoproteins. It appears that glucocorticoids exert their intermediary effects partly via physical interaction with COUP-TFII.