Olig2 is a basic helix-loop-helix (bHLH) transcription factor essential for development of motoneurons and oligodendrocytes. It is known that Olig2+ cells persist in the central nervous system (CNS) from embryonic to adult stages and that the number of Olig2+ progenitors increases in the injured adult CNS. Recent studies have demonstrated an inhibitory action of Olig2 on neurogenesis in adult CNS, but the fate of Olig2+ cells in the injured state remains largely unknown. To trace directly the fate of Olig2 cells in the adult cerebral cortex after injury, we employed the CreER/loxP system to target the olig2 locus. In this genetic tracing study, green fluorescent protein (GFP) reporter-positive cells labeled after cryoinjury coexpressed glial fibrillary acidic protein (GFAP), an astrocytic marker. Electron microscopy also showed that GFP+ cells have the ultrastructural characteristics of astrocytes. Furthermore, GFP+ cells labeled before injury, most of which had been NG2 cells, also produced bushy astrocytes. Here we show direct evidence that Olig2+ cells preferentially differentiate into astrocytes, which strongly express GFAP, in response to injury in the adult cerebral cortex. These results suggest that reactive astrocytes, known to be the main contributors to glial scars, originate, at least in part, from Olig2+ cells. © 2008 Wiley-Liss, Inc.