The small G protein ADP-ribosylation factor 6 (Arf6) plays important roles in a wide variety of membrane dynamics-based cellular events such as neurite outgrowth and spine formation in vitro. However, little is known about physiological function of Arf6 in vivo. Here we generate conditional knockout mice lacking Arf6 in neurons, oligodendrocytes, or both cell lineages, and unexpectedly find that Arf6 expression in neurons, but not in oligodendrocytes, is crucial for oligodendrocyte myelination in the hippocampal fimbria and the corpus callosum during development, and that this is through the regulation of secretion of fibroblast growth factor-2, a guidance factor for migration of oligodendrocyte precursor cells (OPCs). These results suggest that Arf6 in neurons plays an important role in OPC migration through regulation of FGF-2 secretion during neuronal development.