COUP-TFs are orphan members of the steroid/thyroid hormone receptor superfamily. COUP-TF homologues have been cloned in several species, from Drosophila to man. The vertebrate COUP-TFs can be classified into four subgroups according to sequence homology in their ligand-binding domain. COUP-TFs bind to AGGTCA direct repeats or palindromes with various spacings. These include the response elements of several other members of the superfamily, the vitamin D receptor, the thyroid hormone receptor, the retinoic acid receptor, the retinoid X receptor, the peroxisome proliferation activated regulator, and the hepatocyte nuclear factor-4. COUP-TF response elements have been identified in the promoters of many genes and COUP-TFs have been shown to act as negative regulators both in vitro and in vivo. They can compete with the above mentioned receptors for binding to the common response elements. The ratio of COUP-TF and the other positive regulator determines the transcriptional state of the particular gene in any given moment. COUP-TFs are expressed in the developing central nervous system of mouse and zebra-fish. In addition, they are also expressed in many organs during mouse organogenesis. The expression pattern and profile of COUP-TFs favor the hypothesis that they are involved in development and differentiation. The expression of COUP-TFs are also highly regulated. P19 embryonal carcinoma cells have been used as a model system to study COUP-TF regulation. COUP-TFs are up-regulated in retinoic acid (RA) treated P19 cells. Transient transfection assay showed that mouse COUP-TFII promoter directly responded to RA treatment, suggesting that COUP-TF expression is directly regulated by RA signaling pathway.