Chicken ovalbumin upstream promoter-transcription factors (COUP-TFs) are one of the most characterized orphan receptors of the steroid/thyroid hormone receptor superfamily. COUP-TFs play important roles in the regulation of organogenesis, neurogenesis, and cellular differentiation during embryonic development. COUP-TFs were generally considered to be repressors of transcription, however, there are growing evidences that COUP-TFs can function as transcription activators. Here we will review the molecular mechanism of COUP-TFs as repressors and activators. Also, we will review the known biological function of COUP-TFI during development and differentiation.