Molecular mechanisms that control oligodendrocyte myelination during mammalian central nervous system (CNS) development are poorly understood. In this study, we identified Zfp488, an oligodendrocyte-specific zinc-finger transcription regulator, by screening for genes downregulated in the optic nerves of Olig1-null mice. The predicted primary structure of Zfp488 is evolutionarily conserved in vertebrates and invertebrates. In the developing CNS, Zfp488 is specifically expressed in oligodendrocytes but not their precursors. Its expression increases in parallel with that of major myelin genes Mbp and Plp1. Zfp488 is a nuclear protein that possesses transcriptional repression activity. In the developing chick neural tube, Zfp488 can promote oligodendrocyte precursor formation upon Notch activation. In addition, Zfp488 can interact and cooperate with the bHLH transcription factor Olig2 to promote precocious and ectopic oligodendrocyte differentiation. Furthermore, knockdown of Zfp488 via RNAi in an oligodendroglial cell line leads to the downregulation of myelin gene expression. Taken together, these data suggest that Zfp488 functions as an oligodendrocyte-specific transcription co-regulator important for oligodendrocyte maturation and that zinc-finger/bHLH cooperation can serve as a mechanism for oligodendroglial differentiation.