Chicken ovalbumin upstream promoter transcription factors (COUP-TFs) are orphan members of the steroid/thyroid hormone receptor superfamily. They have been shown to negatively regulate the activation function of vitamin D, thyroid hormone, retinoic acid, the retinoid X and the peroxisome proliferator-activated receptors. COUP-TF genes have been cloned from many species and their sequences are exceptionally conserved through evolution. This suggests a critical role for the COUP-TFs in these organisms. Indeed, the Drosophila COUP-TF, seven-up and mouse COUP-TFII are essential for development and differentiation during embryogenesis. Our current understanding of COUP-TF function suggests that they serve vital physiological roles during development despite extensive overlaps of expression. This defines the COUP-TFs as important factors in regulation of development and differentiation in multiple organisms.